Pyrazolopyridines and pyrazolopyrimidines

ABSTRACT

A compound having the structure: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or pharmaceutically acceptable salt, wherein A and A′ are independently C or N, where C may be unsubstituted or substituted by halo or C 1 -C 6  alkyl; R and R 0  are independently selected from the group consisting of H, C 1 -C 6  alkyl, hydroxy(C 1 -C 6  alkyl), phenyl(C 1 -C 6  alkyl), and —(CH 2 ) n —W, where W is C 3 -C 8  cycloalkyl, phenyl, naphthyl, 5- or 6-membered heteroaryl or heterocyclic containing 1-3 N, S and/or O atoms, —SO 2 —R′, —NHSO 2 —R′, —NR″SO 2 —R′ and SR′, where R′ and R″ are independently C 1 -C 6  alkyl or C 3 -C 8  cycloalkyl, etc.; wherein each of said alkyl, cycloalkyl, heterocyclic, phenyl, naphthyl or heteroaryl may be unsubstituted or substituted by phenyl, heteroaryl, etc.; or, R and R 0  and the N atom to which they are bonded together form a monocyclic or bicyclic heterocyclic ring which may be unsubstituted or substituted by (a) halo, hydroxy, heteroaryl, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, etc., or (b) —(CH 2 ) n —W, where W is C 3 -C 8  cycloalkyl, phenyl, etc.; R 1  is H, halo or cyano; R 2  and R 2′  are independently H, C 1 -C 6  alkyl, cyano, C 1 -C 6  alkoxy, C 1 -C 6  alkylthio, or C 3 -C 8  cycloalkyl where alkyl, alkoxy, or cycloalkyl is optionally substituted by one or more fluorine atoms; X is a bond, —CO—, —CONH—, —SO 2 —, —SONH—, or —(CH 2 ) m —; R 3  is H, C 1 -C 4  alkyl, phenyl, naphthyl, 5- or 6-membered heteroaryl or heterocyclic containing 1-3 N atoms, a 5-membered heteroaryl or heterocyclic, etc., or (c) 2 O or S atoms and 0-2 N atoms; wherein each of said phenyl, naphthyl, heteroaryl or heterocyclic is optionally substituted by alkyl, 1 substituent —Y—R 4  and/or 1-4 substituents each independently selected from R 5 ; with the proviso that when X is —CO— or —SO 2 —, R 3  is not H; Y is a bond, —(CH 2 ) m — or —O—; R 4  is (a) H, C 1 -C 6  alkyl, C 3 -C 8  cycloalkyl, halo, oxo, —OR 6 , —NR 7 R 8 , —SR 6 , —SOR 9 , —SO 2 R 9 , —COR 6 , —OCOR 6 , —COOR 6 , —NR 6 COR 6 , —CONR 7 R 8 , etc.; (b) phenyl or naphthyl, said phenyl and naphthyl being optionally substituted with 1-5 substituents selected from C 1 -C 6  alkyl, C 3 -C 8  cycloalkyl, halo, cyano, —OR 6 , —NR 7 R 8 , etc.; or (c) a 3 to 8-membered saturated or partially unsaturated monocyclic heteroaryl, etc.; R 6  is H, C 1 -C 6  alkyl or C 3 -C 8  cycloalkyl, etc.; R 7  and R 8  are each independently H, C 1 -C 6  alkyl or C 3 -C 8  cycloalkyl or are taken together with the nitrogen atom to which they are attached to form a 4-, 5- or 6-membered saturated heterocyclic ring containing 1-2 nitrogen atoms or 1 nitrogen and 1 oxygen atom, said C 1 -C 6  alkyl is optionally substituted by C 3 -C 8  cycloalkyl, halo, etc., and said heterocyclic ring being optionally substituted by one or more C 1 -C 6  alkyl or C 3 -C 8  cycloalkyl groups; R 9  is C 1 -C 6  alkyl or C 3 -C 8  cycloalkyl; and, m and n are independently 0, 1, 2 or 3. The invention also relates to pharmaceutically acceptable salts of these compounds and to pharmaceutically acceptable solvates thereof; to compositions containing such compounds; and to the uses of such compounds in the treatment of various diseases, particularly asthma and COPD.

CROSS REFERENCE TO RELATED APPLICATION

This application claims the priority benefit of U.S. ProvisionalApplication No. 61/993,138, filed May 14, 2014, the entirety of which ishereby incorporated by reference herein.

FIELD OF THE INVENTION

The present invention relates to pyrazolopyridines andpyrazolopyrimidines, pharmaceutical compositions comprising suchcompounds and their use as medicaments. More particularly, the presentinvention provides 6-phenyl-1H-pyrazolopyridines derivatives and6-phenyl-1H-pyrazolopyrimidines derivatives which are Janus Kinase (JAK)inhibitors and useful for the treatment of allergic and respiratoryconditions, particularly chronic obstructive pulmonary disease.

BACKGROUND

Chronic obstructive pulmonary disease (COPD) is the fourth leading causeof death in the US and is characterized by airflow obstruction that isnot fully reversible with bronchodilators. The airflow limitation isusually progressive and is associated with an abnormal inflammatoryresponse of the lungs to noxious particles or gases, primarily cigarettesmoke. Symptoms are typically breathing-related (e.g. chronic cough,exertional dyspnea, expectoration and wheeze). Patients experienceperiods of stable disease interspersed with inflammatory exacerbationsresulting in acute decline in lung function and often hospitalization.

Current treatment guidelines recommend bronchodilators as the mainstayof COPD drug treatment. However, anti-inflammatory inhaledcorticosteroids (ICS) and bronchodilator/inhaled corticosteroidcombination products, are extensively used. Whilst inhaledcorticosteroids do provide some benefits with respect to short term lungfunction improvements and exacerbation frequency, they do not addressthe corticosteroid-refractory inflammation which is characteristic ofthis disease and thought to play a key role in disease progression.There is a clear medical need for anti-inflammatory therapies in COPDthat will address the chronic inflammatory component of the disease andultimately provide symptomatic relief, a reduction in exacerbationfrequency and an amelioration of exacerbation severity.

The Janus kinase (JAK) family of receptor associated tyrosine kinases,JAK 1, JAK 2, JAK 3 and tyrosine kinase 2 (TYK2), are involved in signaltransduction associated with a variety of inflammatory cytokines. JAKkinases can function as either hetero or homo-dimers, phosphorylatingSTAT transcription factors which regulate inflammatory genetranscription. Oral JAK 1/JAK 3 inhibitors such as CP-690550 have shownimpressive anti-inflammatory activity in inflammatory diseases such asrheumatoid arthritis and psoriasis.

Many JAK dependent cytokines are thought to play key roles in thepathology of COPD which involves the interplay of multiple inflammatorycells such as T lymphocytes, neutrophils, macrophages and lungepithelium. For example the JAK 1/JAK 3 heterodimer plays a key role inT lymphocyte survival and activation whereas JAK 2 is thought to becritical for regulation of neutrophil activation and apoptosis. JAK 1and JAK 2 play an important role in IL-13 mediated inflammatorysignaling in macrophages, which is thought to link acute inflammatoryevents to chronic progressive disease. Importantly JAK 1, JAK 2 and TYK2 also play an important role in signaling mediated by IFNγ, a cytokineassociated with the chronic inflammation observed in COPD, whichmodulates the activity of T cells, epithelium and macrophages whilst notbeing modulated by corticosteroids.

Macrophage phagocytosis of bacteria is impaired in the lungs of COPDpatients, potentially in part due to high local IFNγ levels. In vitrostudies with isolated patient cells have shown that JAK inhibitorsincrease phagocytotic rate in the presence of IFNγ. Consequently, aswell as exerting a direct anti-inflammatory effect, JAK inhibitors mayalso increase the ability of the lung to maintain a sterile environment.

JAK inhibitors are therefore likely to have utility in the treatment ofa range of inflammatory diseases, including lung diseases such as COPD,asthma and pulmonary vascular disease. Compounds which have a broadinhibitory activity across the range of Janus kinases, in particular,are likely to have a potent anti-inflammatory effect. However, such aselectivity profile can also lead to undesirable side-effects insystemically circulating compounds, particularly anemia and neutropeniaassociated with JAK 2 inhibition. For the treatment of lung diseases, itis therefore particularly favorable to provide JAK inhibitors which canbe administered by inhalation and which inhibit Janus kinases locally inthe lung without having a significant systemic exposure.

There is thus a need to provide new JAK inhibitors that are potent,selective inhibitors of Janus kinases with appropriate metabolicstability and pharmacokinetic properties, particularly compounds whichcan be administered by inhalation and are active in lung tissue whilsthaving poor systemic penetration or high systemic lability.

SUMMARY OF THE INVENTION

The present invention provides pyrazolopyridines and pyrazolopyrimidineswhich are potent and selective inhibitors of Janus kinases, including acompound having the structure:

or a pharmaceutically acceptable salt thereof, or a pharmaceuticallyacceptable solvate of said compound or pharmaceutically acceptable salt,wherein A and A′ are independently C or N, where C may be unsubstitutedor substituted by halo or C₁-C₆ alkyl;

R and R⁰ are independently selected from the group consisting of H,C₁-C₆ alkyl, hydroxy(C₁-C₆ alkyl), phenyl(C₁-C₆ alkyl), and—(CH₂)_(n)—W, where W is C₃-C₈ cycloalkyl, phenyl, naphthyl, 5- or6-membered heteroaryl or heterocyclic containing 1-3 N, S and/or Oatoms, —SO₂—R′, —NHSO₂—R′, —NR″SO₂—R′ and SR′, where R′ and R″ areindependently C₁-C₆ alkyl or C₃-C₈ cycloalkyl, amino, C₁-C₆ alkylamino,di(C₁-C₆ alkyl)amino, phenyl, heteroaryl, or heterocyclic; wherein eachof said alkyl, cycloalkyl, heterocyclic, phenyl, naphthyl or heteroarylmay be unsubstituted or substituted by phenyl, heteroaryl, heterocyclic,halo, cyano, hydroxy, C₁-C₆ alkyl, C₁-C₆ alkoxy, aryloxy, —SO₂—R′,—CONR′R″, NR′COR″, —NR′CONR′R″, —NR′CO₂R″, —(CH₂)_(n)—SO₂—R′, —NHSO₂—R′,—NR″SO₂—R′ or SR′ where R′ and R″ are independently C₁-C₆ alkyl, C₃-C₆cycloalkyl, phenyl, amino, hydroxyalkylamino, heterocyclic, or—(CH₂)_(n)—W′, where W′ is hydroxy, C₃-C₈ cycloalkyl, phenyl, naphthyl,heterocyclic, or 5- or 6-membered heteroaryl containing 1-3 N, S and/orO atoms;

or, R and R⁰ and the N atom to which they are bonded together form amonocyclic or bicyclic heterocyclic ring which may be unsubstituted orsubstituted by (a) halo, hydroxy, heteroaryl, C₁-C₆ alkyl, C₁-C₆ alkoxy,(C₁-C₆ alkoxy)C₁-C₆ alkoxy, aryl(C₁-C₆ alkoxy), aryloxy, amino,aminoacyl, C₁-C₆ alkylaminoacyl, arylalkylaminoacyl, di(C₁-C₆alkyl)aminoacyl, —SO₂—R′, —SO₂—NR″—(CH₂)_(n)—W, —NHSO₂—R′, —NR″SO₂—R′ orSR′ where R′ and R″ is independently amino, C₁-C₆ alkylamino, di(C₁-C₆alkyl)amino, C₁-C₆ alkyl or C₃-C₈ cycloalkyl, or (b) —(CH₂)_(n)—W, whereW is C₃-C₈ cycloalkyl, phenyl, naphthyl, heterocyclic, 5- or 6-memberedheteroaryl containing 1-3 N atoms, —SO₂—R′, —NHSO₂—R′, —NR″SO₂—R′ orSR′, where R′ and R″ is independently alkyl or cycloalkyl; wherein eachof said phenyl, aryl, or heteroaryl may be unsubstituted or substitutedby halo, C₁-C₆ alkyl, C₁-C₆ alkoxy, cyano, or hydroxy;

R¹ is H, cyano or halo; R² and R^(2′) are independently H, C₁-C₆ alkyl,cyano, C₁-C₆ alkoxy, C₁-C₆ alkylthio, or C₃-C₈ cycloalkyl where alkyl,alkoxy, or cycloalkyl is optionally substituted by one or more fluorineatoms;

X is a bond, —CO—, —CONH—, —SO₂—, —SONH—, or —(CH₂)_(m)—;

R³ is H, C₁-C₄ alkyl, phenyl, naphthyl, 6-membered heteroaryl orheterocyclic containing 1-3 N atoms, a 5-membered heteroaryl orheterocyclic containing either (a) 1-4 N atoms or (b) 1 O or S atom and0-3 N atoms, a 10-membered bicyclic heteroaryl or heterocycliccontaining 1-4 N atoms, a 9-membered bicyclic heteroaryl or heterocycliccontaining either (a) 1-4 N atoms or (b) 1 O or S atom and 0-3 N atoms,or an 8-membered bicyclic heteroaryl or heterocyclic containing (a) 1-4N atoms or (b) 1 O or S atom and 1-3 N atoms or (c) 2 O or S atoms and0-2 N atoms; wherein each of said phenyl, naphthyl, heteroaryl orheterocyclic is optionally substituted by alkyl, 1 substituent —Y—R⁴and/or 1-4 substituents each independently selected from R⁵; with theproviso that when X is —CO— or —SO₂—, R³ is not H;

Y is a bond, —(CH₂)_(m)— or —O—;

R⁴ is (a) H, C₁-C₆ alkyl, C₃-C₈ cycloalkyl, halo, oxo, —OR⁶, —NR⁷R⁸,—SR⁶, —SOR⁹, —SO₂R⁹, —COR⁶, —OCOR⁶, —COOR⁶, —NR⁶COR⁶, —CONR⁷R⁸,—NR⁶SO₂R⁹, —SO₂NR⁷R⁸, —NR⁶CONR⁷R⁸, —NR⁶COOR⁹ and —NR⁶SO₂NR⁷R⁸; (b)phenyl or naphthyl, said phenyl and naphthyl being optionallysubstituted with 1-5 substituents selected from C₁-C₆ alkyl, C₃-C₈cycloalkyl, halo, —CN, —OR⁶, —NR⁷R⁸, —SR⁶, —SOR⁹, —SO₂R⁹, —COR⁶, —OCOR⁶,—COOR⁶, —NR⁶COR⁶, —CONR⁷R⁸, —NR⁶SO₂R⁹, —SO₂NR⁷R⁸, —NR⁶CONR⁷R⁸, —NR⁶COOR⁹and —NR⁶SO₂NR⁷R⁸; or (c) a 3 to 8-membered saturated or partiallyunsaturated monocyclic heteroaryl, containing 1 or 2 heteroatomsselected from O and N, said heteroaryl being optionally substituted by1-5 substituents selected from C₁-C₆ alkyl, C₃-C₈ cycloalkyl, halo, oxo,—OR⁶, —NR⁷R⁸, —SR⁶, —SOR⁹, —SO₂R⁹, —COR⁶, —OCOR⁶, —COOR⁶, —NR⁶COR⁶,—CONR⁷R⁸, —NR⁶SO₂R⁹, —SO₂NR⁷R⁸, —NR⁶CONR⁷R⁸, —NR⁶COOR⁹ and —NR⁶SO₂NR⁷R⁸;

R⁵ is C₁-C₆ alkyl, C₃-C₈ cycloalkyl, halo, cyano, —OR⁶, —NR⁷R⁸, —SR⁶,—SOR⁹, —SO₂R⁹, —COR⁶, —OCOR⁶, —COOR⁶, —NR⁶COR⁶, —CONR⁷R⁸, —NR⁶SO₂R⁹,—SO₂NR⁷R⁸, —NR⁶CONR⁷R⁸, —NR⁶COOR⁹ or —NR⁶SO₂NR⁷R⁸;

R⁶ is H, C₁-C₆ alkyl or C₃-C₈ cycloalkyl, said C₁-C₆ alkyl is optionallysubstituted by —NR⁷R⁸ or a 3 to 8-membered saturated or partiallyunsaturated monocyclic heteroaryl, containing 1 or 2 heteroatomsselected from O and N, said heteroaryl being optionally substituted by1-5 substituents selected from C₁-C₆ alkyl, C₃-C₈ cycloalkyl, halo,cyano, hydroxy and cyano;

R⁷ and R⁸ are each independently H, C₁-C₆ alkyl or C₃-C₈ cycloalkyl orare taken together with the nitrogen atom to which they are attached toform a 4-, 5- or 6-membered saturated heterocyclic ring containing 1-2nitrogen atoms or 1 nitrogen and 1 oxygen atom, said C₁-C₆ alkyl isoptionally substituted by C₃-C₈ cycloalkyl, halo, cyano, hydroxy, amino,(C₁-C₆ alkyl)amino or di(C₁-C₆ alkyl)amino and said heterocyclic ringbeing optionally substituted by one or more C₁-C₆ alkyl or C₃-C₈cycloalkyl groups;

R⁹ is C₁-C₆ alkyl or C₃-C₈ cycloalkyl; and, m and n are independently 0,1, 2 or 3.

The invention also provides a compound of formula (Ia) having thestructure:

or a pharmaceutically acceptable salt thereof, or a pharmaceuticallyacceptable solvate of said compound or pharmaceutically acceptable salt,wherein:

A, A″ and A′″ are independently C or N, where C may be unsubstituted orsubstituted by halo or C₁-C₆ alkyl;

R¹ is H, cyano or halo;

R² and R^(2′) are independently H, C₁-C₆ alkyl, cyano, C₁-C₆ alkoxy,C₁-C₆ alkylthio, or C₃-C₈ cycloalkyl where alkyl, alkoxy, or cycloalkylis optionally substituted by one or more fluorine atoms;

R³ is H, C₁-C₄ alkyl, phenyl, naphthyl, 6-membered heteroaryl orheterocyclic containing 1-3 N atoms, a 5-membered heteroaryl orheterocyclic containing either (a) 1-4 N atoms or (b) 1 O or S atom and0-3 N atoms, a 10-membered bicyclic heteroaryl or heterocycliccontaining 1-4 N atoms, a 9-membered bicyclic heteroaryl or heterocycliccontaining either (a) 1-4 N atoms or (b) 1 O or S atom and 0-3 N atoms,or an 8-membered bicyclic heteroaryl or heterocyclic containing (a) 1-4N atoms or (b) 1 O or S atom and 1-3 N atoms or (c) 2 O or S atoms and0-2 N atoms; wherein each of said phenyl, naphthyl, heteroaryl orheterocyclic is optionally substituted by alkyl, 1 substituent —Y—R⁴and/or 1-4 substituents each independently selected from R⁵;

Y is a bond, —(CH₂)_(m)— or —O—;

R⁴ is (a) H, C₁-C₆ alkyl, C₃-C₈ cycloalkyl, halo, oxo, —OR⁶, —NR⁷R⁸,—SR⁶, —SOR⁹, —SO₂R⁹, —COR⁶, —OCOR⁶, —COOR⁶, —NR⁶COR⁶, —CONR⁷R⁸,—NR⁶SO₂R⁹, —SO₂NR⁷R⁸, —NR⁶CONR⁷R⁸, —NR⁶COOR⁹ and —NR⁶SO₂NR⁷R⁸; (b)phenyl or naphthyl, said phenyl and naphthyl being optionallysubstituted with 1-5 substituents selected from C₁-C₆ alkyl, C₃-C₈cycloalkyl, halo, —CN, —OR⁶, —NR⁷R⁸, —SR⁶, —SOR⁹, —SO₂R⁹, —COR⁶, —OCOR⁶,—COOR⁶, —NR⁶COR⁶, —CONR⁷R⁸, —NR⁶SO₂R⁹, —SO₂NR⁷R⁸, —NR⁶CONR⁷R⁸, —NR⁶COOR⁹and —NR⁶SO₂NR⁷R⁸; or (c) a 3 to 8-membered saturated or partiallyunsaturated monocyclic heteroaryl, containing 1 or 2 heteroatomsselected from O and N, said heteroaryl being optionally substituted by1-5 substituents selected from C₁-C₆ alkyl, C₃-C₈ cycloalkyl, halo, oxo,—OR⁶, —NR⁷R⁸, —SR⁶, —SOR⁹, —SO₂R⁹, —COR⁶, —OCOR⁶, —COOR⁶, —NR⁶COR⁶,—CONR⁷R⁸, —NR⁶SO₂R⁹, —SO₂NR⁷R⁸, —NR⁶CONR⁷R⁸, —NR⁶COOR⁹ and —NR⁶SO₂NR⁷R⁸;

R⁵ is C₁-C₆ alkyl, C₃-C₈ cycloalkyl, halo, cyano, —OR⁶, —NR⁷R⁸, —SR⁶,—SOR⁹, —SO₂R⁹, —COR⁶, —OCOR⁶, —COOR⁶, —NR⁶COR⁶, —CONR⁷R⁸, —NR⁶SO₂R⁹,—SO₂NR⁷R⁸, —NR⁶CONR⁷R⁸, —NR⁶COOR⁹ or —NR⁶SO₂NR⁷R⁸;

R⁶ is H, C₁-C₆ alkyl or C₃-C₈ cycloalkyl, said C₁-C₆ alkyl is optionallysubstituted by —NR⁷R⁸ or a 3 to 8-membered saturated or partiallyunsaturated monocyclic heteroaryl, containing 1 or 2 heteroatomsselected from O and N, said heteroaryl being optionally substituted by1-5 substituents selected from C₁-C₆ alkyl, C₃-C₈ cycloalkyl, halo,hydroxy and cyano;

R⁷ and R⁸ are each independently H, C₁-C₆ alkyl or C₃-C₈ cycloalkyl orare taken together with the nitrogen atom to which they are attached toform a 4-, 5- or 6-membered saturated heterocyclic ring containing 1-2nitrogen atoms or 1 nitrogen and 1 oxygen atom, said C₁-C₆ alkyl isoptionally substituted by C₃-C₈ cycloalkyl, halo, cyano, hydroxy, amino,(C₁-C₆ alkyl)amino or di(C₁-C₆ alkyl)amino and said heterocyclic ringbeing optionally substituted by one or more C₁-C₆ alkyl or C₃-C₈cycloalkyl groups;

R⁹ is C₁-C₆ alkyl or C₃-C₈ cycloalkyl;

R¹⁰ is —NHSO₂—R′, —NR″SO₂—R′ or SR′ where R′ and R″ are independentlyhydrogen, C₁-C₆ alkyl, C₃-C₈ cycloalkyl, phenyl, amino, C₁-C₆alkylamino, di(C₁-C₆ alkyl)amino, heterocyclic, —(CH₂)_(n)—W′, where W′is hydroxy, C₃-C₈ cycloalkyl, phenyl, naphthyl, heterocyclic, 5- or6-membered heteroaryl containing 1-3 N and/or O atoms; wherein each ofsaid alkyl, cycloalkyl, heterocyclic, phenyl, naphthyl or heteroaryl maybe unsubstituted or substituted by phenyl, heteroaryl, heterocyclic,halo, cyano, hydroxy, C₁-C₆ alkyl, C₁-C₆ alkoxy, aryloxy, —SO₂—R′,—NHSO₂—R′, —NR″SO₂—R′ or SR′ where R′ and R″ are independently phenyl,C₁-C₆ alkyl or C₃-C₈ cycloalkyl;

R¹¹ and R¹² are each independently H, hydroxy, halo, cyano, C₁-C₆ alkylor C₃-C₈ cycloalkyl; and, m and n are independently 0, 1, 2, or 3.

The invention further provides a compound of formula (Ib) having thestructure:

or a pharmaceutically acceptable salt thereof, or a pharmaceuticallyacceptable solvate of said compound or pharmaceutically acceptable salt,wherein:

A″ and A′″ are independently C or N, where C may be unsubstituted orsubstituted by halo or C₁-C₆ alkyl;

R¹ is H, cyano or halo;

R² and R^(2′) are independently H, C₁-C₆ alkyl, cyano, C₁-C₆ alkoxy,C₁-C₆ alkylthio, or C₃-C₈ cycloalkyl where alkyl, alkoxy, or cycloalkylis optionally substituted by one or more fluorine atoms;

R³ is H, C₁-C₄ alkyl, phenyl, naphthyl, 6-membered heteroaryl orheterocyclic containing 1-3 N atoms, a 5-membered heteroaryl orheterocyclic containing either (a) 1-4 N atoms or (b) 1 O or S atom and0-3 N atoms, a 10-membered bicyclic heteroaryl or heterocycliccontaining 1-4 N atoms, a 9-membered bicyclic heteroaryl or heterocycliccontaining either (a) 1-4 N atoms or (b) 1 O or S atom and 0-3 N atoms,or an 8-membered bicyclic heteroaryl or heterocyclic containing (a) 1-4N atoms or (b) 1 O or S atom and 1-3 N atoms or (c) 2 O or S atoms and0-2 N atoms; wherein each of said phenyl, naphthyl, heteroaryl orheterocyclic is optionally substituted by alkyl, 1 substituent —Y—R⁴and/or 1-4 substituents each independently selected from R⁵;

Y is a bond, —(CH₂)_(m)— or —O—;

R⁴ is (a) H, C₁-C₆ alkyl, C₃-C₈ cycloalkyl, halo, oxo, —OR⁶, —NR⁷R⁸,—SR⁶, —SOR⁹, —SO₂R⁹, —COR⁶, —OCOR⁶, —COOR⁶, —NR⁶COR⁶, —CONR⁷R⁸,—NR⁶SO₂R⁹, —SO₂NR⁷R⁸, —NR⁶CONR⁷R⁸, —NR⁶COOR⁹ and —NR⁶SO₂NR⁷R⁸; (b)phenyl or naphthyl, said phenyl and naphthyl being optionallysubstituted with 1-5 substituents selected from C₁-C₆ alkyl, C₃-C₈cycloalkyl, halo, —CN, —OR⁶, —NR⁷R⁸, —SR⁶, —SOR⁹, —SO₂R⁹, —COR⁶, —OCOR⁶,—COOR⁶, —NR⁶COR⁶, —CONR⁷R⁸, —NR⁶SO₂R⁹, —SO₂NR⁷R⁸, —NR⁶CONR⁷R⁸, —NR⁶COOR⁹and —NR⁶SO₂NR⁷R⁸; or (c) a 3 to 8-membered saturated or partiallyunsaturated monocyclic heteroaryl, containing 1 or 2 heteroatomsselected from O and N, said heteroaryl being optionally substituted by1-5 substituents selected from C₁-C₆ alkyl, C₃-C₈ cycloalkyl, halo, oxo,—OR⁶, —NR⁷R⁸, —SR⁶, —SOR⁹, —SO₂R⁹, —COR⁶, —OCOR⁶, —COOR⁶, —NR⁶COR⁶,—CONR⁷R⁸, —NR⁶SO₂R⁹, —SO₂NR⁷R⁸, —NR⁶CONR⁷R⁸, —NR⁶COOR⁹ and —NR⁶SO₂NR⁷R⁸;

R⁵ is C₁-C₆ alkyl, C₃-C₈ cycloalkyl, halo, cyano, —OR⁶, —NR⁷R⁸, —SR⁶,—SOR⁹, —SO₂R⁹, —COR⁶, —OCOR⁶, —COOR⁶, —NR⁶COR⁶, —CONR⁷R⁸, —NR⁶SO₂R⁹,—SO₂NR⁷R⁸, —NR⁶CONR⁷R⁸, —NR⁶COOR⁹ or —NR⁶SO₂NR⁷R⁸;

R⁶ is H, C₁-C₆ alkyl or C₃-C₈ cycloalkyl, said C₁-C₆ alkyl is optionallysubstituted by —NR⁷R⁸ or a 3 to 8-membered saturated or partiallyunsaturated monocyclic heteroaryl, containing 1 or 2 heteroatomsselected from O and N, said heteroaryl being optionally substituted by1-5 substituents selected from C₁-C₆ alkyl, C₃-C₈ cycloalkyl, halo,hydroxy and cyano;

R⁷ and R⁸ are each independently H, C₁-C₆ alkyl or C₃-C₈ cycloalkyl orare taken together with the nitrogen atom to which they are attached toform a 4-, 5- or 6-membered saturated heterocyclic ring containing 1-2nitrogen atoms or 1 nitrogen and 1 oxygen atom, said C₁-C₆ alkyl isoptionally substituted by C₃-C₈ cycloalkyl, halo, cyano, hydroxy, amino,(C₁-C₆ alkyl)amino or di(C₁-C₆ alkyl)amino and said heterocyclic ringbeing optionally substituted by one or more C₁-C₆ alkyl or C₃-C₈cycloalkyl groups;

R⁹ is C₁-C₆ alkyl or C₃-C₈ cycloalkyl;

R¹⁰ is —NHSO₂—R′, —NR″SO₂—R′ or SR′ where R′ and R″ are independentlyhydrogen, C₁-C₆ alkyl, C₃-C₈ cycloalkyl, phenyl, amino, C₁-C₆alkylamino, di(C₁-C₆ alkyl)amino, heterocyclic, —(CH₂)_(n)—W′, where W′is hydroxy, C₃-C₆ cycloalkyl, phenyl, naphthyl, heterocyclic, 5- or6-membered heteroaryl containing 1-3 N and/or O atoms; wherein each ofsaid alkyl, cycloalkyl, heterocyclic, phenyl, naphthyl or heteroaryl maybe unsubstituted or substituted by phenyl, heteroaryl, heterocyclic,halo, cyano, hydroxy, C₁-C₆ alkyl, C₁-C₆ alkoxy, aryloxy, —SO₂—R′,—NHSO₂—R′, —NR″SO₂—R′ or SR′ where R′ and R″ are independently phenyl,C₁-C₆ alkyl or C₃-C₈ cycloalkyl;

R¹¹ and R¹² are each independently H, hydroxy, halo, cyano, C₁-C₆ alkylor C₃-C₈ cycloalkyl; and, m and n are independently 0, 1, 2 or 3. Inanother embodiment, the invention provides the compound of formula Ibwherein R¹⁰ is —NR″SO₂—R′ and R′ and R″ are both C₁-C₆ alkyl.

The invention also provides a compound of formula (Ic) having thestructure:

or a pharmaceutically acceptable salt thereof, or a pharmaceuticallyacceptable solvate of said compound or pharmaceutically acceptable salt,wherein:

R¹ is H, cyano or halo;

R² and R^(2′) are independently H, C₁-C₆ alkyl, cyano, C₁-C₆ alkoxy,C₁-C₆ alkylthio, or C₃-C₈ cycloalkyl where alkyl, alkoxy, or cycloalkylis optionally substituted by one or more fluorine atoms;

R³ is H, C₁-C₄ alkyl, phenyl, naphthyl, 6-membered heteroaryl orheterocyclic containing 1-3 N atoms, a 5-membered heteroaryl orheterocyclic containing either (a) 1-4 N atoms or (b) 1 O or S atom and0-3 N atoms, a 10-membered bicyclic heteroaryl or heterocycliccontaining 1-4 N atoms, a 9-membered bicyclic heteroaryl or heterocycliccontaining either (a) 1-4 N atoms or (b) 1 O or S atom and 0-3 N atoms,or an 8-membered bicyclic heteroaryl or heterocyclic containing (a) 1-4N atoms or (b) 1 O or S atom and 1-3 N atoms or (c) 2 O or S atoms and0-2 N atoms; wherein each of said phenyl, naphthyl, heteroaryl orheterocyclic is optionally substituted by alkyl, 1 substituent —Y—R⁴and/or 1-4 substituents each independently selected from R⁵;

Y is a bond, —(CH₂)_(m)— or —O—;

R⁴ is (a) H, C₁-C₆ alkyl, C₃-C₈ cycloalkyl, halo, oxo, —OR⁶, —NR⁷R⁸,—SR⁶, —SOR⁹, —SO₂R⁹, —COR⁶, —OCOR⁶, —COOR⁶, —NR⁶COR⁶, —CONR⁷R⁸,—NR⁶SO₂R⁹, —SO₂NR⁷R⁸, —NR⁶CONR⁷R⁸, —NR⁶COOR⁹ and —NR⁶SO₂NR⁷R⁸; (b)phenyl or naphthyl, said phenyl and naphthyl being optionallysubstituted with 1-5 substituents selected from C₁-C₆ alkyl, C₃-C₈cycloalkyl, halo, —CN, —OR⁶, —NR⁷R⁸, —SR⁶, —SOR⁹, —SO₂R⁹, —COR⁶, —OCOR⁶,—COOR⁶, —NR⁶COR⁶, —CONR⁷R⁸, —NR⁶SO₂R⁹, —SO₂NR⁷R⁸, —NR⁶CONR⁷R⁸, —NR⁶COOR⁹and —NR⁶SO₂NR⁷R⁸; or (c) a 3 to 8-membered saturated or partiallyunsaturated monocyclic heteroaryl, containing 1 or 2 heteroatomsselected from O and N, said heteroaryl being optionally substituted by1-5 substituents selected from C₁-C₆ alkyl, C₃-C₈ cycloalkyl, halo, oxo,—OR⁶, —NR⁷R⁸, —SR⁶, —SOR⁹, —SO₂R⁹, —COR⁶, —OCOR⁶, —COOR⁶, —NR⁶COR⁶,—CONR⁷R⁸, —NR⁶SO₂R⁹, —SO₂NR⁷R⁸, —NR⁶CONR⁷R⁸, —NR⁶COOR⁹ and —NR⁶SO₂NR⁷R⁸;

R⁵ is C₁-C₆ alkyl, C₃-C₈ cycloalkyl, halo, cyano, —OR⁶, —NR⁷R⁸, —SR⁶,—SOR⁹, —SO₂R⁹, —COR⁶, —OCOR⁶, —COOR⁶, —NR⁶COR⁶, —CONR⁷R⁸, —NR⁶SO₂R⁹,—SO₂NR⁷R⁸, —NR⁶CONR⁷R⁸, —NR⁶COOR⁹ or —NR⁶SO₂NR⁷R⁸;

R⁶ is H, C₁-C₆ alkyl or C₃-C₈ cycloalkyl, said C₁-C₆ alkyl is optionallysubstituted by —NR⁷R⁸ or a 3 to 8-membered saturated or partiallyunsaturated monocyclic heteroaryl, containing 1 or 2 heteroatomsselected from O and N, said heteroaryl being optionally substituted by1-5 substituents selected from C₁-C₆ alkyl, C₃-C₈ cycloalkyl, halo,cyano, hydroxy and cyano;

R⁷ and R⁸ are each independently H, C₁-C₆ alkyl or C₃-C₈ cycloalkyl orare taken together with the nitrogen atom to which they are attached toform a 4-, 5- or 6-membered saturated heterocyclic ring containing 1-2nitrogen atoms or 1 nitrogen and 1 oxygen atom, said C₁-C₆ alkyl isoptionally substituted by C₃-C₈ cycloalkyl, halo, cyano, hydroxy, amino,(C₁-C₆ alkyl)amino or di(C₁-C₆ alkyl)amino and said heterocyclic ringbeing optionally substituted by one or more C₁-C₆ alkyl or C₃-C₈cycloalkyl groups;

R⁹ is C₁-C₆ alkyl or C₃-C₈ cycloalkyl;

R¹⁰ is —NHSO₂—R′, —NR″SO₂—R′ or SR′ where R′ and R″ are independentlyhydrogen, C₁-C₆ alkyl, C₃-C₈ cycloalkyl, phenyl, amino, C₁-C₆alkylamino, di(C₁-C₆ alkyl)amino, heterocyclic, —(CH₂)_(n)—W′, where W′is hydroxy, C₃-C₅ cycloalkyl, phenyl, naphthyl, heterocyclic, 5- or6-membered heteroaryl containing 1-3 N and/or O atoms; wherein each ofsaid alkyl, cycloalkyl, heterocyclic, phenyl, naphthyl or heteroaryl maybe unsubstituted or substituted by phenyl, heteroaryl, heterocyclic,halo, cyano, hydroxy, C₁-C₆ alkyl, C₁-C₆ alkoxy, aryloxy, —SO₂—R′,—NHSO₂—R′, —NR″SO₂—R′ or SR′ where R′ and R″ are independently phenyl,C₁-C₆ alkyl or C₃-C₈ cycloalkyl;

R¹¹ and R¹² are each independently H, hydroxy, halo, cyano, C₁-C₆ alkylor C₃-C₈ cycloalkyl; and, m and n are independently 0, 1, 2 or 3. Incertain embodiments, the invention provides a compound of formula Icwherein R¹⁰ is —NR″SO₂—R′ and R′ and R″ are both C₁-C₆ alkyl.

The invention additionally provides the compound of formula (Id) havingthe structure:

or a pharmaceutically acceptable salt thereof, or a pharmaceuticallyacceptable solvate of said compound or pharmaceutically acceptable salt,wherein:

A and A′ are independently C or N, where C may be unsubstituted orsubstituted by C₁-C₆ alkyl;

R and R⁰ are independently selected from the group consisting of H,C₁-C₆ alkyl, hydroxy(C₁-C₆ alkyl), phenyl(C₁-C₆ alkyl), and—(CH₂)_(n)—W, where W is C₃-C₈ cycloalkyl, phenyl, naphthyl, 5- or6-membered heteroaryl or heterocyclic containing 1-3 N, S and/or Oatoms, —SO₂—R′, —NHSO₂—R′, —NR″SO₂—R′ and SR′, where R′ and R″ areindependently C₁-C₆ alkyl or C₃-C₈ cycloalkyl, amino, C₁-C₆ alkylamino,di(C₁-C₆ alkyl)amino, phenyl, heteroaryl, or heterocyclic; wherein eachof said alkyl, cycloalkyl, heterocyclic, phenyl, naphthyl or heteroarylmay be unsubstituted or substituted by phenyl, heteroaryl, heterocyclic,halo, cyano, hydroxy, C₁-C₆ alkyl, C₁-C₆ alkoxy, aryloxy, —SO₂—R′,—CONR′R″, NR′COR″, —NR′CONR′R″, —NR′CO₂R″, —(CH₂)_(n)—SO₂—R′, —NHSO₂—R′,—NR″SO₂—R′ or SR′ where R′ and R″ are independently C₁-C₆ alkyl, C₃-C₈cycloalkyl, phenyl, amino, hydroxyalkylamino, heterocyclic, or—(CH₂)_(n)—W′, where W′ is hydroxy, C₃-C₈ cycloalkyl, phenyl, naphthyl,heterocyclic, or 5- or 6-membered heteroaryl containing 1-3 N, S and/orO atoms;

or, R and R⁰ and the N atom to which they are bonded together form amonocyclic or bicyclic heterocyclic ring which may be unsubstituted orsubstituted by (a) halo, hydroxy, heteroaryl, C₁-C₆ alkyl, C₁-C₆ alkoxy,(C₁-C₆ alkoxy)C₁-C₆ alkoxy, aryl(C₁-C₆ alkoxy), aryloxy, amino,aminoacyl, C₁-C₆ alkylaminoacyl, arylalkylaminoacyl, di(C₁-C₆alkyl)aminoacyl, —SO₂—R′, —SO₂—NR″—(CH₂)_(n)—W, —NHSO₂—R′, —NR″SO₂—R′ orSR′ where R′ and R″ is independently amino, C₁-C₆ alkylamino, di(C₁-C₆alkyl)amino, C₁-C₆ alkyl or C₃-C₈ cycloalkyl, or (b) —(CH₂)_(n)—W, whereW is C₃-C₈ cycloalkyl, phenyl, naphthyl, heterocyclic, 5- or 6-memberedheteroaryl containing 1-3 N atoms, —SO₂—R′, —NHSO₂—R′, —NR″SO₂—R′ orSR′, where R′ and R″ is independently alkyl or cycloalkyl; wherein eachof said phenyl, aryl, or heteroaryl may be unsubstituted or substitutedby halo, C₁-C₆ alkyl, C₁-C₆ alkoxy, cyano, or hydroxy;

R¹ is H, cyano or halo; R² and R^(2′) are independently H, C₁-C₆ alkyl,cyano, C₁-C₆ alkoxy, C₁-C₆ alkylthio, or C₃-C₈ cycloalkyl where alkyl,alkoxy, or cycloalkyl is optionally substituted by one or more fluorineatoms; and, n is 0, 1, 2 or 3.

The invention additionally provides the compound of formula (Ie) havingthe structure:

or a pharmaceutically acceptable salt thereof, or a pharmaceuticallyacceptable solvate of said compound or pharmaceutically acceptable salt,wherein:

A, A′, A″ and A′″ are independently C or N, where C may be unsubstitutedor substituted by halo or C₁-C₆ alkyl;

R¹ is H, cyano or halo;

R² and R^(2′) are independently H, C₁-C₆ alkyl, cyano, C₁-C₆ alkoxy,C₁-C₆ alkylthio, or C₃-C₈ cycloalkyl where alkyl, alkoxy, or cycloalkylis optionally substituted by one or more fluorine atoms;

R¹⁰ is —NHSO₂—R′, —NR″SO₂—R′ or SR′ where R′ and R″ is independentlyC₁-C₆ alkyl or C₃-C₈ cycloalkyl; and,

R¹¹ and R¹² are each independently H, hydroxy, halo, cyano, C₁-C₆ alkylor C₃-C₈ cycloalkyl. In certain embodiments, the invention provides acompound having the structure:

or a pharmaceutically acceptable salt thereof, or a pharmaceuticallyacceptable solvate of said compound or pharmaceutically acceptable salt,wherein:

A″ and A′″ are independently C or N, where C may be unsubstituted orsubstituted by halo or C₁-C₆ alkyl;

R¹ is H, cyano or halo;

R² and R^(2′) are independently H, C₁-C₆ alkyl, cyano, C₁-C₆ alkoxy,C₁-C₆ alkylthio, or C₃-C₈ cycloalkyl where alkyl, alkoxy, or cycloalkylis optionally substituted by one or more fluorine atoms;

R¹⁰ is —NHSO₂—R′, —NR″SO₂—R′ or SR′ where R′ and R″ are independentlyhydrogen, C₁-C₆ alkyl, C₃-C₈ cycloalkyl, phenyl, amino, C₁-C₆alkylamino, di(C₁-C₆ alkyl)amino, heterocyclic, —(CH₂)_(n)—W′, where W′is hydroxy, C₃-C₈ cycloalkyl, phenyl, naphthyl, heterocyclic, 5- or6-membered heteroaryl containing 1-3 N and/or O atoms; wherein each ofsaid alkyl, cycloalkyl, heterocyclic, phenyl, naphthyl or heteroaryl maybe unsubstituted or substituted by phenyl, heteroaryl, heterocyclic,halo, cyano, hydroxy, C₁-C₆ alkyl, C₁-C₆ alkoxy, aryloxy, —SO₂—R′,—NHSO₂—R′, —NR″SO₂—R′ or SR′ where R′ and R″ are independently phenyl,C₁-C₆ alkyl or C₃-C₈ cycloalkyl;

R¹¹ and R¹² are each independently H, hydroxy, halo, cyano, C₁-C₆ alkylor C₃-C₈ cycloalkyl; and, m and n are independently 0, 1, 2 or 3.

The also provides the compound of formula (Ig) having the structure:

or a pharmaceutically acceptable salt thereof, or a pharmaceuticallyacceptable solvate of said compound or pharmaceutically acceptable salt,wherein:

R¹ is H, cyano or halo;

R² and R^(2′) are independently H, C₁-C₆ alkyl, cyano, C₁-C₆ alkoxy,C₁-C₆ alkylthio, or C₃-C₈ cycloalkyl where alkyl, alkoxy, or cycloalkylis optionally substituted by one or more fluorine atoms;

R¹⁰ is —NHSO₂—R′, —NR″SO₂—R′ or SR′ where R′ and R″ are independentlyhydrogen, C₁-C₆ alkyl, C₃-C₈ cycloalkyl, phenyl, amino, C₁-C₆alkylamino, di(C₁-C₆ alkyl)amino, heterocyclic, —(CH₂)_(n)—W′, where W′is hydroxy, C₃-C₈ cycloalkyl, phenyl, naphthyl, heterocyclic, 5- or6-membered heteroaryl containing 1-3 N and/or O atoms; wherein each ofsaid alkyl, cycloalkyl, heterocyclic, phenyl, naphthyl or heteroaryl maybe unsubstituted or substituted by phenyl, heteroaryl, heterocyclic,halo, cyano, hydroxy, C₁-C₆ alkyl, C₁-C₆ alkoxy, aryloxy, —SO₂—R′,—NHSO₂—R′, —NR″SO₂—R′ or SR′ where R′ and R″ are independently phenyl,C₁-C₆ alkyl or C₃-C₈ cyclo alkyl; and, n is 0, 1, 2 or 3. In certainembodiments, the invention provides the compound of formula Ig whereinR¹⁰ is —NR″SO₂—R′ and R′ and R″ are both C₁-C₆ alkyl.

The invention also provides the compound of formula (Ih) having thestructure:

or a pharmaceutically acceptable salt thereof, or a pharmaceuticallyacceptable solvate of said compound or pharmaceutically acceptable salt,wherein:

A and A′ are independently C or N, where C may be unsubstituted orsubstituted by halo or C₁-C₆ alkyl;

R and R⁰ are independently selected from the group consisting of H,C₁-C₆ alkyl, hydroxy(C₁-C₆ alkyl), phenyl(C₁-C₆ alkyl), and—(CH₂)_(n)—W, where W is C₃-C₈ cycloalkyl, phenyl, naphthyl, 5- or6-membered heteroaryl or heterocyclic containing 1-3 N, S and/or Oatoms, —SO₂—R′, —NHSO₂—R′, —NR″SO₂—R′ and SR′, where R′ and R″ areindependently C₁-C₆ alkyl or C₃-C₈ cycloalkyl, amino, C₁-C₆ alkylamino,di(C₁-C₆ alkyl)amino, phenyl, heteroaryl, or heterocyclic; wherein eachof said alkyl, cycloalkyl, heterocyclic, phenyl, naphthyl or heteroarylmay be unsubstituted or substituted by phenyl, heteroaryl, heterocyclic,halo, cyano, hydroxy, C₁-C₆ alkyl, C₁-C₆ alkoxy, aryloxy, —SO₂—R′,—CONR′R″, NR′COR″, —NR′CONR′R″, —NR′CO₂R″, —(CH₂)_(n)—SO₂—R′, —NHSO₂—R′,—NR″SO₂—R′ or SR′ where R′ and R″ are independently C₁-C₆ alkyl, C₃-C₈cycloalkyl, phenyl, amino, hydroxyalkylamino, heterocyclic, or—(CH₂)_(n)—W, where W is hydroxy, C₃-C₈ cycloalkyl, phenyl, naphthyl,heterocyclic, or 5- or 6-membered heteroaryl containing 1-3 N, S and/orO atoms;

or, R and R⁰ and the N atom to which they are bonded together form amonocyclic or bicyclic heterocyclic ring which may be unsubstituted orsubstituted by (a) halo, hydroxy, heteroaryl, C₁-C₆ alkyl, C₁-C₆ alkoxy,(C₁-C₆ alkoxy)C₁-C₆ alkoxy, aryl(C₁-C₆ alkoxy), aryloxy, amino,aminoacyl, C₁-C₆ alkylaminoacyl, arylalkylaminoacyl, di(C₁-C₆alkyl)aminoacyl, —SO₂—R′, —SO₂—NR″—(CH₂)_(n)—W, —NHSO₂—R′, —NR″SO₂—R′ orSR′ where R′ and R″ is independently amino, C₁-C₆ alkylamino, di(C₁-C₆alkyl)amino, C₁-C₆ alkyl or C₃-C₈ cycloalkyl, or (b) —(CH₂)_(n)—W, whereW is C₃-C₈ cycloalkyl, phenyl, naphthyl, heterocyclic, 5- or 6-memberedheteroaryl containing 1-3 N atoms, —SO₂—R′, —NHSO₂—R′, —NR″SO₂—R′ orSR′, where R′ and R″ is independently alkyl or cycloalkyl; wherein eachof said phenyl, aryl, or heteroaryl may be unsubstituted or substitutedby halo, C₁-C₆ alkyl, C₁-C₆ alkoxy, cyano, or hydroxy;

R¹ is H, cyano or halo;

R² and R^(2′) are independently H, C₁-C₆ alkyl, cyano, C₁-C₆ alkoxy,C₁-C₆ alkylthio, or C₃-C₈ cycloalkyl where alkyl, alkoxy, or cycloalkylis optionally substituted by one or more fluorine atoms;

R³ is H, C₁-C₄ alkyl, phenyl, naphthyl, 6-membered heteroaryl orheterocyclic containing 1-3 N atoms, a 5-membered heteroaryl orheterocyclic containing either (a) 1-4 N atoms or (b) 1 O or S atom and0-3 N atoms, a 10-membered bicyclic heteroaryl or heterocycliccontaining 1-4 N atoms, a 9-membered bicyclic heteroaryl or heterocycliccontaining either (a) 1-4 N atoms or (b) 1 O or S atom and 0-3 N atoms,or an 8-membered bicyclic heteroaryl or heterocyclic containing (a) 1-4N atoms or (b) 1 O or S atom and 1-3 N atoms or (c) 2 O or S atoms and0-2 N atoms; wherein each of said phenyl, naphthyl, heteroaryl orheterocyclic is optionally substituted by alkyl, 1 substituent —Y—R⁴and/or 1-4 substituents each independently selected from R⁵; with theproviso that when X is —CO— or —SO₂—, R³ is not H;

Y is a bond, —(CH₂)_(m)— or —O—;

R⁴ is (a) H, C₁-C₆ alkyl, C₃-C₈ cycloalkyl, halo, oxo, —OR⁶, —NR⁷R⁸,—SR⁶, —SOR⁹, —SO₂R⁹, —COR⁶, —OCOR⁶, —COOR⁶, —NR⁶COR⁶, —CONR⁷R⁸,—NR⁶SO₂R⁹, —SO₂NR⁷R⁸, —NR⁶CONR⁷R⁸, —NR⁶COOR⁹ and —NR⁶SO₂NR⁷R⁸; (b)phenyl or naphthyl, said phenyl and naphthyl being optionallysubstituted with 1-5 substituents selected from C₁-C₆ alkyl, C₃-C₈cycloalkyl, halo, —CN, —OR⁶, —NR⁷R⁸, —SR⁶, —SOR⁹, —SO₂R⁹, —COR⁶, —OCOR⁶,—COOR⁶, —NR⁶COR⁶, —CONR⁷R⁸, —NR⁶SO₂R⁹, —SO₂NR⁷R⁸, —NR⁶CONR⁷R⁸, —NR⁶COOR⁹and —NR⁶SO₂NR⁷R⁸; or (c) a 3 to 8-membered saturated or partiallyunsaturated monocyclic heteroaryl, containing 1 or 2 heteroatomsselected from O and N, said heteroaryl being optionally substituted by1-5 substituents selected from C₁-C₆ alkyl, C₃-C₈ cycloalkyl, halo, oxo,—OR⁶, —NR⁷R⁸, —SR⁶, —SOR⁹, —SO₂R⁹, —COR⁶, —OCOR⁶, —COOR⁶, —NR⁶COR⁶,—CONR⁷R⁸, —NR⁶SO₂R⁹, —SO₂NR⁷R⁸, —NR⁶CONR⁷R⁸, —NR⁶COOR⁹ and —NR⁶SO₂NR⁷R⁸;

R⁵ is C₁-C₆ alkyl, C₃-C₈ cycloalkyl, halo, —CN, —OR⁶, —NR⁷R⁸, —SR⁶,—SOR⁹, —SO₂R⁹, —COR⁶, —OCOR⁶, —COOR⁶, —NR⁶COR⁶, —CONR⁷R⁸, —NR⁶SO₂R⁹,—SO₂NR⁷R⁸, —NR⁶CONR⁷R⁸, —NR⁶COOR⁹ or —NR⁶SO₂NR⁷R⁸;

R⁶ is H, C₁-C₆ alkyl or C₃-C₈ cycloalkyl, said C₁-C₆ alkyl is optionallysubstituted by —NR⁷R⁸ or a 3 to 8-membered saturated or partiallyunsaturated monocyclic heteroaryl, containing 1 or 2 heteroatomsselected from O and N, said heteroaryl being optionally substituted by1-5 substituents selected from C₁-C₆ alkyl, C₃-C₈ cycloalkyl, halo,hydroxy and cyano;

R⁷ and R⁸ are each independently H, C₁-C₆ alkyl or C₃-C₈ cycloalkyl orare taken together with the nitrogen atom to which they are attached toform a 4-, 5- or 6-membered saturated heterocyclic ring containing 1-2nitrogen atoms or 1 nitrogen and 1 oxygen atom, said C₁-C₆ alkyl isoptionally substituted by C₃-C₈ cycloalkyl, halo, cyano, hydroxy, amino,(C₁-C₆ alkyl)amino or di(C₁-C₆ alkyl)amino and said heterocyclic ringbeing optionally substituted by one or more C₁-C₆ alkyl or C₃-C₈cycloalkyl groups;

R⁹ is C₁-C₆ alkyl or C₃-C₈ cycloalkyl; and, m and n are independently 0,1, 2 or 3. In certain embodiments, the invention provides the compoundof formula Ih wherein R¹⁰ is —NR″SO₂—R′ and R′ and R″ are both C₁-C₆alkyl.

The invention also provides the compound of formula (Ii) having thestructure:

or a pharmaceutically acceptable salt thereof, or a pharmaceuticallyacceptable solvate of said compound or pharmaceutically acceptable salt,wherein:

R¹ is H, cyano or halo;

R² and R^(2′) are independently H, C₁-C₆ alkyl, cyano, C₁-C₆ alkoxy,C₁-C₆ alkylthio, or C₃-C₈ cycloalkyl where alkyl, alkoxy, or cycloalkylis optionally substituted by one or more fluorine atoms;

R³ is H, C₁-C₄ alkyl, phenyl, naphthyl, 6-membered heteroaryl orheterocyclic containing 1-3 N atoms, a 5-membered heteroaryl orheterocyclic containing either (a) 1-4 N atoms or (b) 1 O or S atom and0-3 N atoms, a 10-membered bicyclic heteroaryl or heterocycliccontaining 1-4 N atoms, a 9-membered bicyclic heteroaryl or heterocycliccontaining either (a) 1-4 N atoms or (b) 1 O or S atom and 0-3 N atoms,or an 8-membered bicyclic heteroaryl or heterocyclic containing (a) 1-4N atoms or (b) 1 O or S atom and 1-3 N atoms or (c) 2 O or S atoms and0-2 N atoms; wherein each of said phenyl, naphthyl, heteroaryl orheterocyclic is optionally substituted by alkyl, 1 substituent —Y—R⁴and/or 1-4 substituents each independently selected from R⁵;

Y is a bond, —(CH₂)_(m)— or —O—;

R⁴ is (a) H, C₁-C₆ alkyl, C₃-C₈ cycloalkyl, halo, oxo, —OR⁶, —NR⁷R⁸,—SR⁶, —SOR⁹, —SO₂R⁹, —COR⁶, —OCOR⁶, —COOR⁶, —NR⁶COR⁶, —CONR⁷R⁸,—NR⁶SO₂R⁹, —SO₂NR⁷R⁸, —NR⁶CONR⁷R⁸, —NR⁶COOR⁹ and —NR⁶SO₂NR⁷R⁸; (b)phenyl or naphthyl, said phenyl and naphthyl being optionallysubstituted with 1-5 substituents selected from C₁-C₆ alkyl, C₃-C₈cycloalkyl, halo, cyano, —OR⁶, —NR⁷R⁸, —SR⁶, —SOR⁹, —SO₂R⁹, —COR⁶,—OCOR⁶, —COOR⁶, —NR⁶COR⁶, —CONR⁷R⁸, —NR⁶SO₂R⁹, —SO₂NR⁷R⁸, —NR⁶CONR⁷R⁸,—NR⁶COOR⁹ and —NR⁶SO₂NR⁷R⁸; or (c) a 3 to 8-membered saturated orpartially unsaturated monocyclic heteroaryl, containing 1 or 2heteroatoms selected from O and N, said heteroaryl being optionallysubstituted by 1-5 substituents selected from C₁-C₆ alkyl, C₃-C₈cycloalkyl, halo, cyano, oxo, —OR⁶, —NR⁷R⁸, —SR⁶, —SOR⁹, —SO₂R⁹, —COR⁶,—OCOR⁶, —COOR⁶, —NR⁶COR⁶, —CONR⁷R⁸, —NR⁶SO₂R⁹, —SO₂NR⁷R⁸, —NR⁶CONR⁷R⁸,—NR⁶COOR⁹ and —NR⁶SO₂NR⁷R⁸;

R⁵ is C₁-C₆ alkyl, C₃-C₈ cycloalkyl, halo, —CN, —OR⁶, —NR⁷R⁸, —SR⁶,—SOR⁹, —SO₂R⁹, —COR⁶, —OCOR⁶, —COOR⁶, —NR⁶COR⁶, —CONR⁷R⁸, —NR⁶SO₂R⁹,—SO₂NR⁷R⁸, —NR⁶CONR⁷R⁸, —NR⁶COOR⁹ or —NR⁶SO₂NR⁷R⁸;

R⁶ is H, C₁-C₆ alkyl or C₃-C₈ cycloalkyl, said C₁-C₆ alkyl is optionallysubstituted by —NR⁷R⁸ or a 3 to 8-membered saturated or partiallyunsaturated monocyclic heteroaryl, containing 1 or 2 heteroatomsselected from O and N, said heteroaryl being optionally substituted by1-5 substituents selected from C₁-C₆ alkyl, C₃-C₈ cycloalkyl, halo,hydroxy and cyano;

R⁷ and R⁸ are each independently H, C₁-C₆ alkyl or C₃-C₈ cycloalkyl orare taken together with the nitrogen atom to which they are attached toform a 4-, 5- or 6-membered saturated heterocyclic ring containing 1-2nitrogen atoms or 1 nitrogen and 1 oxygen atom, said C₁-C₆ alkyl isoptionally substituted by C₃-C₈ cycloalkyl, halo, cyano, hydroxy, amino,(C₁-C₆ alkyl)amino or di(C₁-C₆ alkyl)amino and said heterocyclic ringbeing optionally substituted by one or more C₁-C₆ alkyl or C₃-C₈cycloalkyl groups; R⁹ is C₁-C₆ alkyl or C₃-C₈ cycloalkyl;

R¹⁰ is —NHSO₂—R′, —NR″SO₂—R′ or SR′ where R′ and R″ are independentlyhydrogen, C₁-C₆ alkyl, C₃-C₈ cycloalkyl, phenyl, amino, C₁-C₆alkylamino, di(C₁-C₆ alkyl)amino, heterocyclic, —(CH₂)_(n)—W′, where W′is hydroxy, C₃-C₈ cycloalkyl, phenyl, naphthyl, heterocyclic, 5- or6-membered heteroaryl containing 1-3 N and/or O atoms; wherein each ofsaid alkyl, cycloalkyl, heterocyclic, phenyl, naphthyl or heteroaryl maybe unsubstituted or substituted by phenyl, heteroaryl, heterocyclic,halo, cyano, hydroxy, C₁-C₆ alkyl, C₁-C₆ alkoxy, aryloxy, —SO₂—R′,—NHSO₂—R′, —NR″SO₂—R′ or SR′ where R′ and R″ are independently phenyl,C₁-C₆ alkyl or C₃-C₈ cycloalkyl; and, m and n are independently 0, 1, 2or 3.

In certain embodiments, the invention provides a compound of formula Igwherein R¹⁰ is —NR″SO₂—R′ and R′ and R″ are both C₁-C₆ alkyl.

In specific embodiments, the invention provides a compound selected fromthe group consisting of:

-   4-({2-[ethyl(ethylsulfonyl)amino]benzyl}amino)-6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)-phenyl]-N-methyl-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;-   4-({2-[ethyl(ethylsulfonyl)amino]benzyl}amino)-6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-N-methyl-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;-   6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-4-({2-[(ethylsulfonyl)(methyl)amino]benzyl}amino)-N-methyl-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;-   6-(2-ethyl    5-fluoro-4-hydroxyphenyl)-4-{[2-(4-hydroxyphenyl)ethyl]amino}-N-methyl-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;-   6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-N-methyl-4-[(2-methylpropyl)amino]-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;-   4-({5-chloro-2-[methyl(methylsulfonyl)amino]benzyl}amino)-6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-N-methyl-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;-   6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-4-({5-fluoro-2-[methyl(methylsulfonyl)amino]benzyl}amino)-N-methyl-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;-   6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-4-({2-fluoro-6-[methyl(methylsulfonyl)amino]benzyl}amino)-N-methyl-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;-   6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-4-({2-[ethyl(methylsulfonyl)amino]benzyl}amino)-N-methyl-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;-   4-[(cyclopentylmethyl)amino]-6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-N-methyl-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;-   6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-N-methyl-4-({5-methyl-2-[methyl(methylsul-fonyl)amino]benzyl}amino)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;-   4-({2-[ethyl(methylsulfonyl)amino]benzyl}amino)-6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoro-ethyl)phenyl]-N-methyl-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;-   4-({2-[(ethylsulfonyl)(methyl)amino]benzyl}amino)-6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-N-methyl-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;-   6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-4-({5-fluoro-2-[methyl(methylsulfonyl)amino]benzyl}amino)-N-methyl-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;-   4-({5-chloro-2-[methyl(methylsulfonyl)amino]benzyl}amino)-6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-N-methyl-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;-   6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-N-methyl-4-[(2-methylpropyl)amino]-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;-   4-[(cyclopentylmethyl)amino]-6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-N-methyl-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;-   6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-4-({2-fluoro-6-[methyl(methylsulfonyl)-amino]benzyl}amino)-N-methyl-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;-   6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-N-methyl-4-({2-[methyl(methylsulfonyl)amino]benzyl}-amino)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;-   6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-N-methyl-4-({2-[methyl(methylsulfonyl)-amino]benzyl}amino)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;-   6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-N-methyl-4-({5-methyl-2-[methyl(methylsulfonyl)amino]-benzyl}amino)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;-   6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-N-methyl-4-({2-[methyl(phenylsulfonyl)-amino]benzyl}amino)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;-   6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-N-methyl-4-[(2-{4-[(phenylsulfonyl)amino]-phenyl}ethyl)-amino]-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;-   6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-4-({2-[(2-hydroxyethyl)(methylsulfonyl)-amino]benzyl}amino)-N-methyl-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;-   6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-4-({2-[methyl(phenylsulfonyl)amino]benzyl}-amino)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;-   6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-4-({2-[(2-hydroxyethyl)(methylsulfonyl)-amino]benzyl}amino)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;-   6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-4-({4-hydroxy-2-[methyl(methylsulfonyl)amino]benzyl}-amino)-N-methyl-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;-   6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-4-({4-hydroxy-2-[methyl(methylsulfonyl)amino]benzyl}-amino)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;-   6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-4-({5-hydroxy-2-[methyl(methylsulfonyl)amino]benzyl}-amino)-N-methyl-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;-   6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-4-[(2-{[(3-hydroxyphenyl)sulfonyl](methyl)-amino}benzyl)amino]-N-methyl-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;-   6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-4-({4-hydroxy-2-[methyl(methylsulfonyl)-amino]benzyl}amino)-N-methyl-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;-   4-({2-[ethyl(methylsulfonyl)amino]-5-hydroxybenzyl}amino)-6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-N-methyl-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;-   6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-4-({5-hydroxy-2-[methyl(phenylsulfonyl)-amino]benzyl}amino)-N-methyl-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;-   4-({2-[ethyl(phenylsulfonyl)amino]-5-hydroxybenzyl}amino)-6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-N-methyl-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;-   6-(2-cyclopropyl-5-fluoro-4-hydroxyphenyl)-N-methyl-4-({2-[methyl(methylsulfonyl)amino]-benzyl}amino)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;-   6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-N-methyl-4-{[(1R)-1-(2-[methyl(methylsulfonyl)amino]-phenyl)ethyl]amino}-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;-   6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-N-methyl-4-{([(1S)-1-{2-[methyl(methylsulfonyl)-amino]phenyl}ethyl]amino}-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;-   6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-4-({2-[methyl(phenylsulfonyl)amino]benzyl}amino)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;-   6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-4-({4-hydroxy-2-[methyl(methylsulfonyl)-amino]benzyl}amino)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;-   6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-4-({5-hydroxy-2-[methyl(phenylsulfonyl)-amino]benzyl}amino)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;-   4-({2-[ethyl(phenylsulfonyl)amino]-5-hydroxybenzyl}amino)-6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;-   6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-N-methyl-4-[({3-[methyl(phenylsulfonyl)-amino]pyrazin-2-yl}methyl)amino]-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;-   4-[({3-[ethyl(methylsulfonyl)amino]pyrazin-2-yl}methyl)amino]-6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-N-methyl-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;-   N-ethyl-4-[({3-[ethyl(methylsulfonyl)amino]pyrazin-2-yl}methyl)amino]-6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;-   6-(2-cyclopropyl-5-fluoro-4-hydroxyphenyl)-4-({2-[methyl(methylsulfonyl)amino]benzyl}amino)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;-   6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-N-methyl-4-[({4-[methyl(methylsulfonyl)-amino]pyridin-3-yl}methyl)amino]-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;-   6-(2-cyclopropyl-5-fluoro-4-hydroxyphenyl)-N-methyl-4-[({2-[methyl(methylsulfonyl)amino]-pyridin-3-yl}methyl)amino]-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;-   6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-4-({5-methoxy-2-[methyl(methylsulfonyl)-amino]benzyl}amino)-N-methyl-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;-   6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-N-methyl-4-[({3-[methyl(methylsulfonyl)amino]pyrazin-2-yl}methyl)amino]-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;-   4-[({2-[ethyl(methylsulfonyl)amino]pyridin-3-yl}methyl)amino]-6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;-   6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-N-methyl-4-[({2-[methyl(methylsulfonyl)-amino]pyridin-3-yl}methyl)amino]-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;-   6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-4-({5-hydroxy-2-[methyl(pyridin-3-ylsulfonyl)amino]benzyl}amino)-N-methyl-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;-   6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-N-methyl-4-[({3-[methyl(methylsulfonyl)-amino]pyridin-2-yl}methyl)amino]-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;-   6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-4-({2-[methyl(methylsulfonyl)amino]benzyl}amino)-N-(6-methylpyridin-3-yl)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;-   6-(5-fluoro-hydroxy-2-(2,2,2-trifluoroethyl)phenyl)-N-methyl-4-((1,3,3-trimethylureido)benzyl)-amino)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;-   6-(5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl)-N-methyl-4-((2-(N-methyl-1H-pyrazole-4-sulfonamido)benzyl)amino)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;-   4-((2-N,1-dimethyl-1H-imidazole-4-sulfonamido)benzyl)amido)-6-(5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl)-N-methyl-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;-   6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-4-[(2-{[(2-methoxyethyl)sulfonyl]-(methyl)amino}benzyl)amino]-N-methyl-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;-   6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-4-({2-[methyl(pyridin-3-ylsulfonyl)amino]benzyl}amino)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;-   6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-4-[({2-[methyl(methylsulfonyl)amino]pyridin-3-yl}methyl)amino]-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;-   4-[({2-[ethyl(methylsulfonyl)amino]pyridin-3-yl}methyl)amino]-6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-N-methyl-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;-   6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-N-methyl-4-{[2-(sulfamoylmethyl)benzyl]-amino}-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;-   6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-4-{[2-(methyl{[6-(morpholin-4-yl)pyridin-3-yl]sulfonyl}amino)benzyl]amino}-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;-   6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-4-{[2-(methyl{[3-(morpholin-4-yl)propyl]sulfonyl}amino)benzyl]amino}-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;-   6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-N-methyl-4-[({5-methyl-2-[methyl(methyl-sulfonyl)amino]pyridin-3-yl}methyl)amino]-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;-   6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-N-methyl-4-({2-[methyl(pyridin-3-ylsulfonyl)amino]benzyl}amino)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;-   6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-N-methyl-4-[(2-{methyl[(6-methylpyridin-3-yl)sulfonyl]amino}benzyl)amino]-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;-   6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-4-[(2-{methyl[(6-methylpyridin-3-yl)sulfonyl]amino}benzyl)amino]-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;-   4-[({5-chloro-2-[ethyl(methylsulfonyl)amino]pyridin-3-yl}methyl)amino]-6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;-   4-[({5-chloro-2-[methyl(methylsulfonyl)amino]pyridin-3-yl}methyl)amino]-6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;-   6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-N-methyl-4-({2-[methyl(sulfamoyl)amino]benzyl}amino)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;-   6-(5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl)-4-((N-(2-hydroxyethyl)sulfamoyl)(methyl)-aminobenzyl)amino)-N-methyl-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;-   6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-N-{6-[(2-hydroxyethyl)amino]pyridin-3-yl}-4-({5-hydroxy-2-[methyl(methylsulfonyl)amino]benzyl}amino)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;-   6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-4-({2-[methyl(methylsulfonyl)amino]benzyl}amino)-N-(6-methylpyridin-3-yl)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;-   6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-4-({2-[methyl(methylsulfonyl)-amino]benzyl}amino)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;-   6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-4-[({5-fluoro-2-[methyl(methylsulfonyl)-amino]pyridin-3-yl}methyl)amino]-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;-   4-[({2-[ethyl(methylsulfonyl)amino]-5-fluoropyridin-3-yl}methyl)amino]-6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;-   4-[({3-[ethyl(methylsulfonyl)amino]pyrazin-2-yl}methyl)amino]-6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;-   6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-4-({5-methyl-2-[methyl(methylsulfonyl)-amino]benzyl}amino)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;-   4-((2-(N-ethylethylsulfonamido)benzyl)amino)-6-(5-fluoro-hydroxy-2-(2,2,2-trifluoroethyl)phenyl)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;-   4-((2-(N-ethylmethylsulfonamido)-5-fluorobenzyl)amino)-6-(5-fluoro-4-hydroxy-2-(2,2,2-trifluoro-ethyl)phenyl)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;-   4-((5-chloro-2-(N-ethylmethylsulfonamido)benzyl)amino)-6-(5-fluoro-4-hydroxy-2-(2,2,2-trifluoro-ethyl)phenyl)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;-   6-(5-fluoro-hydroxy-2-(2,2,2-trifluoroethyl)phenyl)-4-((2-(N-methylethyl-sulfonamido)benzyl)-amino)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;-   6-(5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl)-4-(((5-methyl-2-(N-methylmethylsulfonamido)pyridin-3-yl)methyl)amino)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;-   4-[({2-[ethyl(methylsulfonyl)amino]-5-methylpyridin-3-yl}methyl)amino]-6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;-   6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-4-({5-fluoro-2-[methyl(methylsulfonyl)-amino]benzyl}amino)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;-   4-({5-chloro-2-[methyl(methylsulfonyl)amino]benzyl}amino)-6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;-   4-({2-[ethyl(methylsulfonyl)amino]benzyl}amino)-6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)-phenyl]-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;-   4-({2-[ethyl(methylsulfonyl)amino]-5-methylbenzyl}amino)-6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;-   6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-4-({5-hydroxy-2-[methyl(methylsulfonyl)-amino]benzyl}amino)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;-   6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-N-methyl-4-((2-(N-methylmethylsulfonamido)benzyl)-amino)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide;-   6-(5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl)-N-methyl-4-((2-(N-methylmethylsulfonamido)benzyl)amino)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide;-   6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-4-((2-(N-methylphenylsulfonamido)benzyl)amino)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide;-   6-(5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl)-4-((2-(N-methyiphenylsulfonamido)-benzyl)amino)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide;-   6-(5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl)-4-((5-hydroxy-2-(N-methylmethylsulfonamido)benzyl)amino)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide;-   6-(5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl)-4-((2-(N-methylmethylsulfonamido)benzyl)amino)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide;-   6-(5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl)-4-((5-hydroxy-2-(N-methylmethylsulfonamido)benzyl)amino)-N-(6-((2-hydroxyethyl)amino)pyridin-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide;-   6-(5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl)-N-methyl-4-(((3-(N-methylmethylsulfonamido)pyrazin-2-yl)methyl)amino)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide;-   6-(5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl)-4-((2-(N-(2-hydroxyethyl)methyl-sulfonamido)benzyl)amino)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide;-   6-(5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl)-4-((2-(N-(2-hydroxyethyl)methylsulfonamido)benzyl)amino)-N-methyl-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide;-   4-((2-(N-ethylmethylsulfonamido)benzyl)amino)-6-(5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)-phenyl)-N-methyl-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide;-   4-((5-fluoro-2-(N-methylmethylsulfonamido)benzyl)amino)-6-(5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl)-N-methyl-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide;-   4-((2-(N-ethylphenylsulfonamido)-5-hydroxybenzyl)amino)-6-(5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl)-N-methyl-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide;-   4-((2-(N-methylphenylsulfonamido)-5-hydroxybenzyl)amino)-6-(5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl)-N-methyl-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide;-   4-((2-(N-ethylphenylsulfonamido)-5-hydroxybenzyl)amino)-6-(5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide;-   4-((2-(N-methylphenylsulfonamido)-5-hydroxybenzyl)amino)-6-(5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide;-   6-(5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl)-N-methyl-4-((2-(methyl(sulfamoyl)amino)-benzyl)amino)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide;-   6-(5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl)-N-methyl-4-((2-(methyl(N-methylsulfamoyl)amino)benzyl)amino)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide;-   4-[4-(7,8-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl]-3-ethylphenol    formate;-   3-ethyl-4-[4-(3-phenoxyazetidin-1-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl]phenol    formate;-   3-ethyl-4-{4-[6-(4-methyl-1H-imidazol-1-yl)-3,4-dihydroisoquinolin-2(1H)-yl]-1H-pyrazolo[4,3-c]pyridin-6-yl}phenol    formate;-   3-ethyl-4-{4-[6-(2-methoxyethoxy)-3,4-dihydroisoquinolin-2(1H)-yl]-1H-pyrazolo[4,3-c]pyridin-6-yl}phenol    formate;-   1-[6-(2-ethyl-4-hydroxyphenyl)-1H-pyrazolo[4,3-c]pyridin-4-yl]-3-methylazetidin-3-ol    formate;-   2-[6-(2-ethyl-4-hydroxyphenyl)-1H-pyrazolo[4,3-c]pyridin-4-yl]-N-[2-(pyrrolidin-1-yl)ethyl]-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide    formate;-   N-benzyl-2-[6-(2-ethyl-4-hydroxyphenyl)-1H-pyrazolo[4,3-c]pyridin-4-yl]-1,2,3,4-tetrahydroisoquinoline-5-carbaxamide    formate;-   4-{4-[7-(benzyloxy)-6-methoxy-3,4-dihydroisoquinolin-2(1H)-yl]-1H-pyrazolo[4,3-c]pyridin-6-yl}-3-ethylphenol    formate;-   4-[4-(5-chloro-3,4-dihydroisoquinolin-2(1H)-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl]-3-ethylphenol    formate;-   4-chloro-3-({1-[6-(2-ethyl-4-hydroxyphenyl)-1H-pyrazolo[4,3-c]pyridin-4-yl]azetidin-3-yl}oxy)benzonitnle    formate;-   3-ethyl-4-[4-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl]phenol    formate;-   3-ethyl-A-[4-(8-methoxy-3,4-dihydroisoquinolin-2(1H)-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl]phenol    formate;-   N-{2-[6-(2-ethyl-4-hydroxyphenyl)-1H-pyrazolo[4,3-c]pyridin-4-yl]-1,2,3,4-tetrahydroisoquinolin-5-yl}methanesulfonamide    formate;-   4-(4-{[2-(biphenyl-4-yl)ethyl]amino}-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-ethylphenol    formate;-   N-[2-({[6-(2-ethyl-4-hydroxyphenyl)-1H-pyrazolo[4,3-c]pyridin-4-yl]amino}methyl)phenyl]-N-methylmethanesulfonamide    hydrochloride;-   1-[6-(2-ethyl-4-hydroxyphenyl)-1H-pyrazolo[4,3-c]pyridin-4-yl]-N,    N-dimethylpyrrolidine-3-sulfonamide (racemic);-   N-[2-({[6-(2-ethyl-4-hydroxyphenyl)-1H-pyrazolo[4,3-c]pyridin-4-yl]amino}methyl)-3-methylphenyl]-N-methylmethanesulfonamide    diethylamine salt;-   3-ethyl-4-[4-(4-methoxypiperidin-1-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl]phenol    diethylamine salt;-   N-[2-({[2-(3,4-dimethoxyphenyl)ethyl][6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-pyrazolo[4,3-c]pyridin-4-yl]amino}methyl)phenyl]-N-methylmethanesulfonamide    hydrochloride;-   N-[2-({[6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-pyrazolo[4,3-c]pyridin-4-yl](2-{4-[(methylsulfonyl)amino]phenyl}ethyl)amino}methyl)phenyl]-N-methylmethanesulfonamide    hydrochloride;-   N-[2-({[6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-pyrazolo[4,3-c]pyridin-4-yl]amino}methyl)-phenyl]-N-methylmethanesulfonamide;-   N-[2-({[6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-pyrazolo[4,3-c]pyridin-4-yl]amino}methyl)-4-methylphenyl]-N-methylmethanesulfonamide    hydrochloride;-   N-[4-chloro-2-({[6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-pyrazolo[4,3-c]pyridin-4-yl]amino}methyl)phenyl]-N-methylmethanesulfonamide    hydrochloride;-   N-[2-({[6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-pyrazolo[4,3-c]pyridin-4-yl]amino}methyl)-3-fluorophenyl]-N-methylmethanesulfonamide    hydrochloride;-   N-[2-({[6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-pyrazolo[4,3-c]pyridin-4-yl]amino}methyl)-phenyl]-N-methylethanesulfonamide    hydrochloride;-   N-ethyl-N-[2-({[6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-pyrazolo[4,3-c]pyridin-4-yl]amino}-methyl)phenyl]ethanesulfonamide    hydrochloride;-   N-[2-({[6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-pyrazolo[4,3-c]pyridin-4-yl]amino}methyl)phenyl]-N-propylmethanesulfonamide;-   N-ethyl-N-[2-({[6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-pyrazolo[4,3-c]pyridin-4-yl]amino}-methyl)phenyl]methanesulfonamide;-   N-butyl-N-[2-({[6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-pyrazolo[4,3-c]pyridin-4-yl]amino}-methyl)phenyl]methanesulfonamide;-   N-[2-({[6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-pyrazolo[4,3-c]pyridin-4-yl][2-(morpholin-4-yl)ethyl]amino}methyl)phenyl]-N-methylmethanesulfonamide;-   N-[2-({[6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-pyrazolo[4,3-c]pyridin-4-yl][2-(morpholin-4-yl)ethyl]amino}methyl)phenyl]-N-methylmethanesulfonamide;-   N-ethyl-N-[2-({[6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-pyrazolo[4,3-c]pyridin-4-yl](methyl)-amino}methyl)-4-methylphenyl]methanesulfonamide;-   N-[2-({ethyl[6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-pyrazolo[4,3-c]pyridin-4-yl]amino}methyl)-4-methylphenyl]-N-methylmethanesulfonamide;-   N-[2-({[6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-pyrazolo[4,3-c]pyridin-4-yl](propyl)amino}-methyl)-4-methylphenyl]-N-methylmethanesulfonamide;-   N-ethyl-N-[2-({[6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-pyrazolo[4,3-c]pyridin-4-yl](methyl)amino}methyl)phenyl]methanesulfonamide    hydrochloride;-   N-[2-({[6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-pyrazolo[4,3-c]pyridin-4-yl](methyl)amino}-methyl)phenyl]-N-methylmethanesulfonamide    hydrochloride;-   N-[2-({[6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-pyrazolo[4,3-c]pyridin-4-yl]amino}methyl)phenyl]-N-(2-hydroxyethyl)methanesulfonamide;-   N-{2-[({6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-1H-pyrazolo[4,3-c]pyridin-4-yl}amino)methyl]phenyl}-N-methylmethanesulfonamide;-   N-(2-{[{6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-1H-pyrazolo[4,3-c]pyridin-4-yl}(methyl)amino]methyl}phenyl)-N-methylmethanesulfonamide;-   N-{2-[({6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-1H-pyrazolo[4,3-c]pyridin-4-yl}amino)methyl]-4-methylphenyl}-N-methylmethanesulfonamide;-   4-{4-[(cyclopropylmethyl)amino]-1H-pyrazolo[3,4-d]pyrimidin-6-yl}-2-fluoro-5-(2,2,2-trifluoroethyl)phenol;-   4-{4-[(2-cyclopropylethyl)amino]-1H-pyrazolo[3,4-d]pyrimidin-6-yl}-2-fluoro-5-(2,2,2-trifluoroethyl)phenol;-   2-fluoro-4-{4-[(2-methylpropyl)amino]-1H-pyrazolo[3,4-d]pyrimidin-6-yl}-5-(2,2,2-trifluoro-ethyl)phenol;-   4-[4-(butylamino)-1H-pyrazolo[3,4-d]pyrimidin-6-yl]-2-fluoro-5-(2,2,2-trifluoroethyl)phenol;-   N-[2-({[6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]amino}methyl)-phenyl]-N-methylmethanesulfonamide    hydrochloride;-   N-(2-(((6-(2-ethyl-4-hydroxy-6-methylphenyl)-1H-pyrazolo[4,3-c]pyridin-4-yl)amino)methyl)-phenyl)-N-methylmethanesulfonamide;-   N-[2-({[6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-3-(1H-imidazol-2-yl)-1H-pyrazolo[4,3-c]pyridin-4-yl]amino}methyl)phenyl]-N-methylmethanesulfonamide;-   N-[2-({[3-(4,    5-dimethyl-1H-imidazol-2-yl)-6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-pyrazolo[4,3-c]pyridin-4-yl]amino}methyl)phenyl]-N-methylmethanesulfonamide;-   N-[2-({[6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-3-(4-methyl-1H-imidazol-2-yl)-1H-pyrazolo[4,3-c]pyridin-4-yl]amino}methyl)phenyl]-N-methylmethanesulfonamide;-   4-[3-(5-benzyl-4,5,6,7-tetrahydro-1H-imidazo[4,    5-c]pyridin-2-yl)-4-{[2-(methylsulfanyl)ethyl]-amino}-1H-pyrazolo[4,3-c]pyridin-6-yl]-2-fluoro-5-(2,2,2-trifluoroethyl)phenol;-   N-[2-({[6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-3-(1H-pyrazol-1-yl)-1H-pyrazolo[4,3-c]pyridin-4-yl]amino}methyl)phenyl]-N-methylmethanesulfonamide;-   N-{2-[({6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-3-(1H-pyrazol-1-yl)-1H-pyrazolo[4,3-c]pyridin-4-yl}amino)methyl]phenyl}-N-methylmethanesulfonamide;-   N-{2-[({6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-3-(5-methyl-4H-1,2,4-triazol-3-yl)-1H-pyrazolo[4,3-c]pyridin-4-yl}amino)methyl]phenyl}-N-methylmethanesulfonamide;-   N-[2-({[6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-3-(5-methyl-4H-1,2,4-triazol-3-yl)-1H-pyrazolo[4,3-c]pyridin-4-yl]amino}methyl)phenyl]-N-methylmethanesulfonamide;-   N-{2-[({6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-3-[5-(6-methylpyridin-3-yl)-4H-1,2,4-triazol-3-yl]-1H-pyrazolo[4,3-c]pyridin-4-yl}amino)methyl]phenyl}-N-methylmethanesulfonamide;-   4-(5-{6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-4-({5-hydroxy-2-[methyl(methyl-sulfonyl)amino]benzyl}amino)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-4H-1,2,4-triazol-3-yl)piperidine-1-carboxamide;-   N-(2-[(6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-3-{5-[1-(pyrrolidin-1-ylacetyl)piperidin-4-yl]-4H-1,2,4-triazol-3-yl}-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino]methyl}phenyl)-N-methyl-methanesulfonamide;-   N-{2-[({6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-3-(4,    5,6,7-tetrahydro-1H-imidazo[4,    5-c]pyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl}amino)methyl]-4-hydroxyphenyl}-N-methylmethanesulfonamide;-   N-{2-[({3-(5-acetyl-4,5,6,7-tetrahydro-1H-imidazo[4,    5-c]pyridin-2-yl)-6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-4-yl}amino)methyl]-4-hydroxyphenyl}-N-methylmethanesulfonamide;-   N-[2-(dimethylamino)ethyl]-2-{6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-4-({5-hydroxy-2-[methyl(methylsulfonyl)amino]benzyl}amino)-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-1,4,6,7-tetrahydro-5H-imidazo[4,    5-c]pyridine-5-carboxamide; and,-   4-(3-(5-benzyl-4,5,6,7-tetrahydro-1H-imidazo[4,    5-c]pyridin-2-yl)-4-((3-hydroxy-2-methylpropyl)-amino)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-2-fluoro-5-(2,2,2-trifluoroethyl)phenol.

Preferred embodiments of the invention include:

-   4-({2-[(ethylsulfonyl)(methyl)amino]benzyl}amino)-6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;-   4-({2-[ethyl(ethylsulfonyl)amino]benzyl}amino)-6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;-   4-({2-[ethyl(methylsulfonyl)amino]-5-methylbenzyl}amino)-6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;-   4-({2-[ethyl(methylsulfonyl)amino]-5-fluorobenzyl}amino)-6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;-   4-({2-[ethyl(methylsulfonyl)amino]benzyl}amino)-6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;-   4-({5-chloro-2-[ethyl(methylsulfonyl)amino]benzyl}amino)-6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;-   6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-N-methyl-4-({2-[methyl(methylsulfonyl)amino]benzyl}amino)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;-   6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-4-({5-fluoro-2-[methyl(methylsulfonyl)amino]benzyl}amino)-N-methyl-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;-   6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-4-({5-fluoro-2-[methyl(methylsulfonyl)amino]benzyl}amino)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;    and,-   6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-4-({2-[methyl(methylsulfonyl)amino]benzyl}amino)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;-   or, a pharmaceutically acceptable salt thereof.

More preferred embodiments of the invention include4-({2-[(ethylsulfonyl)-(methyl)amino]benzyl}amino)-6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-1H-pyrazolo[4,3-c]pyridine-3-carboxamide,4-({2-[ethyl(ethylsulfonyl)amino]benzyl}amino)-6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-1H-pyrazolo[4,3-c]pyridine-3-carboxamide,6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoro-ethyl)phenyl]-4-({2-[methyl(methylsulfonyl)amino]benzyl}amino)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide,4-({2-[ethyl(methylsulfonyl)amino]-5-fluorobenz-yl}amino)-6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoro-ethyl)phenyl]-1H-pyrazolo[4,3-c]pyridine-3-carboxamide,4-({2-[ethyl(methylsulfonyl)amino]benzyl}amino)-6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-1H-pyrazolo[4,3-c]pyridine-3-carboxamide,or a pharmaceutically acceptable salt thereof.

In other aspects, the invention provides a pharmaceutical compositioncomprising any pyrazolopyridine and pyrazolopyrimidine compound setforth herein, or a pharmaceutically acceptable salt thereof, or apharmaceutically acceptable solvate of said compound or salt, and apharmaceutically acceptable excipient.

The present invention also provides a method of treating a disease orcondition for which a JAK inhibitor is indicated, in a subject in needof such treatment, comprising administering to the subject atherapeutically effective amount of any compound set forth herein, or apharmaceutically acceptable salt thereof, or a pharmaceuticallyacceptable solvate of said compound or salt.

The present invention further provides a method of treating a disease orcondition selected from allergic rhinitis, nasal congestion, rhinorrhea,perennial rhinitis, nasal inflammation, asthma of all types, chronicobstructive pulmonary disease, chronic or acute bronchoconstriction,chronic bronchitis, small airways obstruction, emphysema, chroniceosinophilic pneumonia, adult respiratory distress syndrome,exacerbation of airways hyper-reactivity consequent to other drugtherapy, pulmonary vascular disease, pulmonary arterial hypertension,acute lung injury, bronchiectasis, sinusitis, allergic conjunctivitis,idiopathic pulmonary fibrosis or atopic dermatitis, comprisingadministering to the subject a therapeutically effective amount of anycompound set forth herein, or a pharmaceutically acceptable saltthereof, or a pharmaceutically acceptable solvate of said compound orsalt.

The present invention also provides a method of treating chronicobstructive pulmonary disease, comprising administering to the subject atherapeutically effective amount of any compound set forth herein, or apharmaceutically acceptable salt thereof, or a pharmaceuticallyacceptable solvate of said compound or salt.

The present invention also provides a method of treating a disease orcondition selected from inflammation, neuroinflammation, arthritis,rheumatoid arthritis, spondyloarthropathies, systemic lupus erythematousarthritis, osteoarthritis, gouty arthritis, pain, fever, pulmonarysarcoisosis, silicosis, cardiovascular disease, atherosclerosis,myocardial infarction, thrombosis, congestive heart failure and cardiacreperfusion injury, cardiomyopathy, stroke, ischaemia, reperfusioninjury, brain edema, brain trauma, neurodegeneration, liver disease,inflammatory bowel disease, Crohn's disease, ulcerative colitis,nephritis, retinitis, retinopathy, macular degeneration, glaucoma,diabetes (type 1 and type 2), diabetic neurorpathy, viral and bacterialinfection, myalgia, endotoxic shock, toxic shock syndrome, autoimmunedisease, osteoporosis, multiple sclerosis, endometriosis, menstrualcramps, vaginitis, candidiasis, cancer, fibrosis, obesity, musculardystrophy, polymyositis, Alzheimer's disease, skin flushing, eczema,psoriasis, atopic dermatitis and sunburn, comprising administering tothe subject a therapeutically effective amount of any compound set forthherein, or a pharmaceutically acceptable salt thereof, or apharmaceutically acceptable solvate of said compound or salt.

The disease or condition for which a JAK inhibitor is indicated ispreferably an allergic or respiratory condition such as allergicrhinitis, nasal congestion, rhinorrhea, perennial rhinitis, nasalinflammation, asthma of all types, chronic obstructive pulmonary disease(COPD), chronic or acute bronchoconstriction, chronic bronchitis, smallairways obstruction, emphysema, chronic eosinophilic pneumonia, adultrespiratory distress syndrome, exacerbation of airways hyper-reactivityconsequent to other drug therapy, pulmonary vasulcar disease (includingpulmonary arterial hypertension), acute lung injury, bronchiectasis,sinusitis, allergic conjunctivitis, idiopathic pulmonary fibrosis oratopic dermatitis, particularly asthma or chronic obstructive pulmonarydisease, most particularly chronic obstructive pulmonary disease.

Other diseases and conditions of interest are inflammation (includingneuroinflammation), arthritis (including rheumatoid arthritis,spondyloarthropathies, systemic lupus erythematous arthritis,osteoarthritis and gouty arthritis), pain, fever, pulmonary sarcoisosis,silicosis, cardiovascular disease (including atherosclerosis, myocardialinfarction, thrombosis, congestive heart failure and cardiac reperfusioninjury), cardiomyopathy, stroke, ischaemia, reperfusion injury, brainedema, brain trauma, neurodegeneration, liver disease, inflammatorybowel disease (including Crohn's disease and ulcerative colitis),nephritis, retinitis, retinopathy, macular degeneration, glaucoma,diabetes (including type 1 and type 2 diabetes), diabetic neurorpathy,viral and bacterial infection, myalgia, endotoxic shock, toxic shocksyndrome, autoimmune disease, osteoporosis, multiple sclerosis,endometriosis, menstrual cramps, vaginitis, candidiasis, cancer,fibrosis, obesity, muscular dystrophy, polymyositis, Alzheimer'sdisease, skin flushing, eczema, psoriasis, atopic dermatitis andsunburn.

Types of asthma include atopic asthma, non-atopic asthma, allergicasthma, atopic bronchial IgE-mediated asthma, bronchial asthma,essential asthma, true asthma, intrinsic asthma caused bypathophysiologic disturbances, extrinsic asthma caused by environmentalfactors, essential asthma of unknown or inapparent cause, bronchiticasthma, emphysematous asthma, exercise-induced asthma, allergen inducedasthma, cold air induced asthma, occupational asthma, infective asthmacaused by bacterial, fungal, protozoal, or viral infection, non-allergicasthma, incipient asthma, wheezy infant syndrome and bronchiolytis.

The treatment of asthma includes palliative treatment for the symptomsand conditions of asthma such as wheezing, coughing, shortness ofbreath, tightness in the chest, shallow or fast breathing, nasal flaring(nostril size increases with breathing), retractions (neck area andbetween or below the ribs moves inward with breathing), cyanosis (grayor bluish tint to skin, beginning around the mouth), runny or stuffynose, and headache.

The present invention also provides any of the uses, methods orcompositions as defined above wherein the compound of formula (I)-(Ii),or pharmaceutically acceptable salt thereof, or pharmaceuticallyacceptable solvate of said compound or salt, is used in combination withanother pharmacologically active compound, particularly one of thefunctionally-defined classes or specific compounds listed below.Generally, the compounds of the combination will be administeredtogether as a formulation in association with one or morepharmaceutically acceptable excipients.

Suitable agents for use in combination therapy with a compound offormula (I)-(Ii), or pharmaceutically acceptable salt thereof, orpharmaceutically acceptable solvate of said compound or salt,particularly in the treatment of respiratory disease, include: a5-lipoxygenase activating protein (FLAP) antagonist; a leukotrieneantagonist (LTRA) such as an antagonist of LTB₄, LTC₄, LTD₄, LTE₄,CysLT₁ or CysLT₂, e.g. montelukast or zafirlukast; a histamine receptorantagonist, such as a histamine type 1 receptor antagonist or ahistamine type 2 receptor antagonist, e.g. loratidine, fexofenadine,desloratidine, levocetirizine, methapyrilene or cetirizine; anal-adrenoceptor agonist or an α2-adrenoceptor agonist, e.g.phenylephrine, methoxamine, oxymetazoline or methylnorephrine; amuscarinic M3 receptor antagonist, e.g. tiotropium or ipratropium; adual muscarinic M3 receptor antagononist/132 agonist; a PDE inhibitor,such as a PDE3 inhibitor, a PDE4 inhibitor or a PDE5 inhibitor, e.g.theophylline, sildenafil, vardenafil, tadalafil, ibudilast, cilomilastor roflumilast; sodium cromoglycate or sodium nedocromil; acyclooxygenase (COX) inhibitor, such as a non-selective inhibitor (e.g.aspirin or ibuprofen) or a selective inhibitor (e.g. celecoxib orvaldecoxib); a glucocorticosteroid, e.g. fluticasone, mometasone,dexamethasone, prednisolone, budesonide, ciclesonide or beclamethasone;an anti-inflammatory monoclonal antibody, e.g. infliximab, adalimumab,tanezumab, ranibizumab, bevacizumab or mepolizumab; a 02 agonist, e.g.salmeterol, albuterol, salbutamol, fenoterol or formoterol, particularlya long-acting β2 agonist; an intigrin antagonist, e.g. natalizumab; anadhesion molecule inhibitor, such as a VLA-4 antagonist; a kinin B₁ orB₂ receptor antagonist; an immunosuppressive agent, such as an inhibitorof the IgE pathway (e.g. omalizumab) or cyclosporine; a matrixmetalloprotease (MMP) inhibitor, such as an inhibitor of MMP-9 orMMP-12; a tachykinin NK₁, NK₂ or NK₃ receptor antagonist; a proteaseinhibitor, such as an inhibitor of elastase, chymase or catheopsin G; anadenosine A28 receptor agonist; an adenosine A2b receptor antagonist; aurokinase inhibitor; a dopamine receptor agonist (e.g. ropinirole),particularly a dopamine D2 receptor agonist (e.g., bromocriptine); amodulator of the NFκB pathway, such as an IKK inhibitor; a furthermodulator of a cytokine signalling pathway such as an inhibitor of JAKkinase, syk kinase, p38 kinase, SPHK-1 kinase, Rho kinase, EGF-R orMK-2; a mucolytic, mucokinetic or anti-tussive agent; an antibiotic; anantiviral agent; a vaccine; a chemokine; an epithelial sodium channel(ENaC) blocker or Epithelial sodium channel (ENaC) inhibitor; anucleotide receptor agonist, such as a P2Y2 agonist; a thromboxaneinhibitor; niacin; a 5-lipoxygenase (5-LO) inhibitor, e.g. Zileuton; anadhesion factor, such as VLAM, ICAM or ELAM; a CRTH2 receptor (DP₂)antagonist; a prostaglandin D₂ receptor (DP₁) antagonist; ahaematopoietic prostaglandin D2 synthase (HPGDS) inhibitor;interferon-β; a soluble human TNF receptor, e.g. Etanercept; a HDACinhibitor; a phosphoinositotide 3-kinase gamma (PI3Kγ) inhibitor; aphosphoinositide 3-kinase delta (PI3Kδ) inhibitor; a CXCR-1 or a CXCR-2receptor antagonist; an IRAK-4 inhibitor; and, a TLR-4 or TLR-9inhibitor, including the pharmaceutically acceptable salts of thespecifically named compounds and the pharmaceutically acceptablesolvates of said specifically named compounds and salts.

Besides being useful for human treatment, compounds of formula (I)-(Ii)are also useful for veterinary treatment of companion animals, exoticanimals and farm animals.

DETAILED DESCRIPTION OF THE INVENTION

Unless otherwise defined herein, scientific and technical terms used inconnection with the present invention have the meanings that arecommonly understood by those of ordinary skill in the art.

The phrase “therapeutically effective” is intended to qualify the amountof compound or pharmaceutical composition, or the combined amount ofactive ingredients in the case of combination therapy. This amount orcombined amount will achieve the goal of treating the relevantcondition.

The term “treatment,” as used herein to describe the present inventionand unless otherwise qualified, means administration of the compound,pharmaceutical composition or combination to effect preventative,palliative, supportive, restorative or curative treatment. The termtreatment encompasses any objective or subjective improvement in asubject with respect to a relevant condition or disease.

The term “preventive treatment,” as used herein to describe the presentinvention, means that the compound, pharmaceutical composition orcombination is administered to a subject to inhibit or stop the relevantcondition from occurring in a subject, particularly in a subject ormember of a population that is significantly predisposed to the relevantcondition.

The term “palliative treatment,” as used herein to describe the presentinvention, means that the compound, pharmaceutical composition orcombination is administered to a subject to remedy signs and/or symptomsof a condition, without necessarily modifying the progression of, orunderlying etiology of, the relevant condition.

The term “supportive treatment,” as used herein to describe the presentinvention, means that the compound, pharmaceutical composition orcombination is administered to a subject as a part of a regimen oftherapy, but that such therapy is not limited to administration of thecompound, pharmaceutical composition or combination.

Unless otherwise expressly stated, supportive treatment may embracepreventive, palliative, restorative or curative treatment, particularlywhen the compounds or pharmaceutical compositions are combined withanother component of supportive therapy.

The term “restorative treatment,” as used herein to describe the presentinvention, means that the compound, pharmaceutical composition orcombination is administered to a subject to modify the underlyingprogression or etiology of a condition. Non-limiting examples include anincrease in forced expiratory volume in one second (FEV 1) for lungdisorders, decreased rate of a decline in lung function over time,inhibition of progressive nerve destruction, reduction of biomarkersassociated and correlated with diseases or disorders, a reduction inrelapses, improvement in quality of life, reduced time spent in hospitalduring an acute exacerbation event and the like.

The term “curative treatment,” as used herein to describe the presentinvention, means that compound, pharmaceutical composition orcombination is administered to a subject for the purpose of bringing thedisease or disorder into complete remission, or that the disease ordisorder is undetectable after such treatment.

The term “selective”, when used to describe a functionally-definedreceptor ligand or enzyme inhibitor means selective for the definedreceptor or enzyme subtype as compared with other receptor or enzymesubtypes in the same family. For instance, a selective PDE5 inhibitor isa compound which inhibits the PDE5 enzyme subtype more potently than anyother PDE enzyme subtype. Such selectivity is preferably at least 2 fold(as measured using conventional binding assays), more preferably atleast 10 fold, most preferably at least 100 fold.

The term “alkyl”, alone or in combination, means an acyclic, saturatedhydrocarbon group of the formula C_(n)H₂₊₁ which may be linear orbranched. Examples of such groups include methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyland hexyl. Unless otherwise specified, an alkyl group comprises from 1to 6 carbon atoms.

The carbon atom content of alkyl and various otherhydrocarbon-containing moieties is indicated by a prefix designating alower and upper number of carbon atoms in the moiety, that is, theprefix C_(i)-C_(j) indicates a moiety of the integer “i” to the integer“j” carbon atoms, inclusive. Thus, for example, C₁-C₆ alkyl refers toalkyl of one to six carbon atoms, inclusive.

The term “hydroxy,” as used herein, means an OH radical.

Het³ is a saturated or partially saturated (i.e. non aromatic)heterocycle and may be attached via a ring nitrogen atom (when theheterocycle is attached to a carbon atom) or a ring carbon atom (in allcases). Equally, when substituted, the substituent may be located on aring nitrogen atom (if the substituent is joined through a carbon atom)or a ring carbon atom (in all cases). Specific examples includeoxiranyl, aziridinyl, oxetanyl, azetidinyl, tetrahydrofuranyl,pyrrolidinyl, tetrahydropyranyl, piperidinyl, 1,4-dioxanyl, morpholinyl,piperazinyl, azepanyl, oxepanyl, oxazepanyl and diazepinyl.

Het³ may be fully saturated or partially unsaturated, i.e. may have oneor more degrees of unsaturation but may not be fully aromatic.

Het¹ is an aromatic heterocycle and may be attached via a ring carbonatom (in all cases) or a ring nitrogen atom with an appropriate valency(when the heterocycle is attached to a carbon atom). Equally, whensubstituted, the substituent may be located on a ring carbon atom (inall cases) or a ring nitrogen atom with an appropriate valency (if thesubstituent is joined through a carbon atom). Specific examples includethienyl, furanyl, pyrrolyl, pyrazolyl, imidazoyl, oxazolyl, isoxazolyl,thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl,tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl and pyrazinyl.

Het² is an aromatic heterocycle and may be attached via a ring carbonatom (in all cases) or a ring nitrogen atom with an appropriate valency(when the heterocycle is attached to a carbon atom). Equally, whensubstituted, the substituent may be located on a ring carbon atom (inall cases) or a ring nitrogen atom with an appropriate valency (if thesubstituent is joined through a carbon atom). Het² is aromatic and istherefore necessarily a fused bicycle. Specific examples includeimidazo[2,1-b][1,3]thiazolyl, benzofuranyl, benzothienyl, indolyl,benzimidazolyl, indazolyl, benzotriazolyl, pyrrolo[2,3-b]pyridyl,pyrrolo[2,3-c]pyridyl, pyrrolo[3,2-c]pyridyl, pyrrolo[3,2-b]pyridyl,imidazo[4,5-b]pyridyl, imidazo[4,5-c]pyridyl, pyrazolo[4,3-d]pyridyl,pyrazolo[4,3-c]pyridyl, pyrazolo[3,4-c]pyridyl, pyrazolo[3,4-b]pyridyl,isoindolyl, indazolyl, purinyl, indolizinyl, imidazo[1,2-a]pyridyl,imidazo[1,5-a]pyridyl, pyrazolo[1,5-a]pyridyl,pyrrolo[1,2-b]pyridazinyl, imidazo[1,2-c]pyrimidinyl, quinolinyl,isoquinolinyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl,1,6-naphthyridinyl, 1,7-naphthyridinyl, 1,8-naphthyridinyl,1,5-naphthyridinyl, 2,6-naphthyridinyl, 2,7-naphthyridinyl,pyrido[3,2-d]pyrimidinyl, pyrido[4,3-d]pyrimidinyl,pyrido[3,4-d]pyrimidinyl, pyrido[2,3-d]pyrimidinyl,pyrido[2,3-d]pyrazinyl, pyrido[3,4-b]pyrazinyl,pyrimido[5,4-d]pyrimidinyl, pyrazino[2,3-b]pyrazinyl andpyrimido[4,5-d]pyrimidine.

The term “cycloalkyl” means a means a monocyclic, saturated hydrocarbongroup of the formula C_(n)H_(2n-1). Examples include cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. Unless otherwisespecified, a cycloalkyl group comprises from 3 to 8 carbon atoms.

The term “oxo” means a doubly bonded oxygen. The term “alkoxy” means aradical comprising an alkyl radical that is bonded to an oxygen atom,such as a methoxy radical. Examples of such radicals include methoxy,ethoxy, propoxy, isopropoxy, butoxy and tert-butoxy. The term “halo”means, fluoro, chloro, bromo or iodo.

As used herein, the terms “co-administration”, “co-administered” and “incombination with”, referring to a combination of a compound of formula(I)-(Ii) and one or more other therapeutic agents, includes thefollowing:

-   -   simultaneous administration of such a combination of a compound        of formula (I)-(Ii) and a further therapeutic agent to a patient        in need of treatment, when such components are formulated        together into a single dosage form which releases said        components at substantially the same time to said patient,    -   substantially simultaneous administration of such a combination        of a compound of formula (I)-(Ii) and a further therapeutic        agent to a patient in need of treatment, when such components        are formulated apart from each other into separate dosage forms        which are taken at substantially the same time by said patient,        whereupon said components are released at substantially the same        time to said patient,    -   sequential administration of such a combination of a compound of        formula (I)-(Ii) and a further therapeutic agent to a patient in        need of treatment, when such components are formulated apart        from each other into separate dosage forms which are taken at        consecutive times by said patient with a significant time        interval between each administration, whereupon said components        are released at substantially different times to said patient;        and    -   sequential administration of such a combination of a compound of        formula (I)-(Ii) and a further therapeutic agent to a patient in        need of treatment, when such components are formulated together        into a single dosage form which releases said components in a        controlled manner.

The term ‘excipient’ is used herein to describe any ingredient otherthan a compound of formula (I)-(Ii). The choice of excipient will to alarge extent depend on factors such as the particular mode ofadministration, the effect of the excipient on solubility and stability,and the nature of the dosage form. The term “excipient” encompassesdiluent, carrier or adjuvant.

One way of carrying out the invention is to administer a compound offormula (I)-(Ii) in the form of a prodrug. Thus, certain derivatives ofa compound of formula (I)-(Ii) which may have little or nopharmacological activity themselves can, when administered into or ontothe body, be converted into a compound of formula (I)-(Ii) having thedesired activity, for example by hydrolytic cleavage, particularlyhydrolytic cleavage promoted by an esterase or peptidase enzyme. Suchderivatives are referred to as ‘prodrugs’. Further information on theuse of prodrugs may be found in ‘Pro-drugs as Novel Delivery Systems’,Vol. 14, ACS Symposium Series (T. Higuchi and W. Stella) and‘Bioreversible Carriers in Drug Design’, Pergamon Press, 1987 (Ed. E. B.Roche, American Pharmaceutical Association). Reference can also be madeto Nature Reviews/Drug Discovery, 2008, 7, 355 and Current Opinion inDrug Discovery and Development, 2007, 10, 550.

Prodrugs in accordance with the invention can, for example, be producedby replacing appropriate functionalities present in the compounds offormula (I)-(Ii) with certain moieties known to those skilled in the artas ‘pro-moieties’ as described, for example, in ‘Design of Prodrugs’ byH. Bundgaard (Elsevier, 1985).

Thus, a prodrug in accordance with the invention is (a) an ester oramide derivative of a carboxylic acid in a compound of formula (I)-(Ii);(b) an ester, carbonate, carbamate, phosphate or ether derivative of ahydroxyl group in a compound of formula (I)-(Ii); (c) an amide, imine,carbamate or amine derivative of an amino group in a compound formformula (I)-(Ii); (d) a thioester, thiocarbonate, thiocarbamate orsulphide derivatives of a thiol group in a compound of formula (I)-(Ii);or (e) an oxime or imine derivative of a carbonyl group in a compound offormula (I)-(Ii).

Some specific examples of prodrugs in accordance with the inventioninclude:

(i) where a compound of formula (I)-(Ii) contains a carboxylic acidfunctionality

(—COOH), an ester thereof, such as a compound wherein the hydrogen ofthe carboxylic acid functionality of the compound of formula (I)-(Ii) isreplaced by C₁-C₈ alkyl (e.g. ethyl) or (C₁-C₈ alkyl)C(═O)OCH₂— (e.g.^(t)BuC(═O)OCH₂—);

(ii) where a compound of formula (I)-(Ii) contains an alcoholfunctionality (—OH), an ester thereof, such as a compound wherein thehydrogen of the alcohol functionality of the compound of formula(I)-(Ii) is replaced by —CO(C₁-C₈ alkyl) (e.g. methylcarbonyl) or thealcohol is esterified with an amino acid;

(iii) where a compound of formula (I)-(Ii) contains an alcoholfunctionality (—OH), an ether thereof, such as a compound wherein thehydrogen of the alcohol functionality of the compound of formula(I)-(Ii) is replaced by (C₁-C₈ alkyl)C(═O)OCH₂— or —CH₂OP(═O)(OH)₂;

(iv) where a compound of formula (I)-(Ii) contains an alcoholfunctionality (—OH), a phosphate thereof, such as a compound wherein thehydrogen of the alcohol functionality of the compound of formula(I)-(Ii) is replaced by —P(═O)(OH)₂ or —P(═O)(ONa)₂ or —P(═O)(O)₂Ca²⁺;

(v) where a compound of formula (I)-(Ii) contains a primary or secondaryamino functionality (—NH₂ or —NHR where R # H), an amide thereof, forexample, a compound wherein, as the case may be, one or both hydrogensof the amino functionality of the compound of formula (I)-(Ii) is/arereplaced by (C₁-C₁₀)alkanoyl, —COCH₂NH₂ or the amino group isderivatised with an amino acid;

(vi) where a compound of formula (I)-(Ii) contains a primary orsecondary amino functionality (—NH₂ or —NHR where R≠H), an aminethereof, for example, a compound wherein, as the case may be, one orboth hydrogens of the amino functionality of the compound of formula(I)-(Ii) is/are replaced by —CH₂OP(═O)(OH)₂.

Certain compounds of formula (I)-(Ii) may themselves act as prodrugs ofother compounds of formula (I)-(Ii). It is also possible for twocompounds of formula (I)-(Ii) to be joined together in the form of aprodrug. In certain circumstances, a prodrug of a compound of formula(I)-(Ii) may be created by internally linking two functional groups in acompound of formula (I)-(Ii), for instance by forming a lactone.

References below to compounds of formula (I)-(Ii) are taken to includethe compounds themselves and prodrugs thereof. The invention includessuch compounds of formula (I)-(Ii) as well as pharmaceuticallyacceptable salts of such compounds and pharmaceutically acceptablesolvates of said compounds and salts. Pharmaceutically acceptable saltsof the compounds of formula (I)-(Ii) include acid addition and basesalts.

Suitable acid addition salts are formed from acids which form non-toxicsalts. Examples include the acetate, adipate, aspartate, benzoate,besylate, bicarbonate/carbonate, bisulfate/sulfate, borate, camsylate,citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate,gluconate, glucuronate, hexafluorophosphate, hibenzate,hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide,isethionate, lactate, malate, maleate, malonate, mesylate,methylsulfate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate,oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogenphosphate, pyroglutamate, saccharate, stearate, succinate, tannate,tartrate, tosylate, trifluoroacetate, naphatlene-1,5-disulfonic acid andxinofoate salts.

Suitable base salts are formed from bases which form non-toxic salts.Examples include the aluminium, arginine, benzathine, calcium, choline,diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine,potassium, sodium, tromethamine and zinc salts.

Hemisalts of acids and bases may also be formed, for example,hemisulfate and hemicalcium salts. For a review on suitable salts, seeHandbook of Pharmaceutical Salts: Properties, Selection, and Use byStahl and Wermuth (Wiley-VCH, 2002).

Pharmaceutically acceptable salts of compounds of formula (I)-(Ii) maybe prepared by one or more of three methods:

(i) by reacting a compound of formula (I)-(Ii) with the desired acid orbase;

(ii) by removing an acid- or base-labile protecting group from asuitable precursor of a compound of formula (I)-(Ii) or by ring-openinga suitable cyclic precursor, for example, a lactone or lactam, using thedesired acid or base; or

(iii) by converting one salt of the compound of formula (I)-(Ii) toanother by reaction with an appropriate acid or base or by means of asuitable ion exchange column.

All three reactions are typically carried out in solution. The resultingsalt may precipitate out and be collected by filtration or may berecovered by evaporation of the solvent. The degree of ionisation in theresulting salt may vary from completely ionised to almost non-ionised.

The compounds of formula (I)-(Ii), and pharmaceutically acceptable saltsthereof, may exist in unsolvated and solvated forms. The term ‘solvate’is used herein to describe a molecular complex comprising the compoundof formula (I)-(Ii), or a pharmaceutically acceptable salt thereof, andone or more pharmaceutically acceptable solvent molecules, for example,ethanol. The term ‘hydrate’ may be employed when said solvent is water.

A currently accepted classification system for organic hydrates is onethat defines isolated site, channel, or metal-ion coordinatedhydrates—see Polymorphism in Pharmaceutical Solids by K. R. Morris (Ed.H. G. Brittain, Marcel Dekker, 1995). Isolated site hydrates are ones inwhich the water molecules are isolated from direct contact with eachother by intervening organic molecules. In channel hydrates, the watermolecules lie in lattice channels where they are next to other watermolecules. In metal-ion coordinated hydrates, the water molecules arebonded to the metal ion.

When the solvent or water is tightly bound, the complex will have awell-defined stoichiometry independent of humidity. When, however, thesolvent or water is weakly bound, as in channel solvates and hygroscopiccompounds, the water/solvent content will be dependent on humidity anddrying conditions. In such cases, non-stoichiometry will be the norm.

Also included within the scope of the invention are multi-componentcomplexes (other than salts and solvates) wherein the drug and at leastone other component are present in stoichiometric or non-stoichiometricamounts. Complexes of this type include clathrates (drug-host inclusioncomplexes) and co-crystals. The latter are typically defined ascrystalline complexes of neutral molecular constituents which are boundtogether through non-covalent interactions, but could also be a complexof a neutral molecule with a salt. Co-crystals may be prepared by meltcrystallization, by recrystallization from solvents, or by physicallygrinding the components together. Cf. Chem. Commun., 17, 1889-1896, byO. Almarsson and M. J. Zaworotko (2004). For a general review ofmulti-component complexes, see J. Pharm. Sci., 64 (8), 1269-1288, byHaleblian (1975).

The compounds of the invention may exist in a continuum of solid statesranging from fully amorphous to fully crystalline. The term ‘amorphous’refers to a state in which the material lacks long range order at themolecular level and, depending upon temperature, may exhibit thephysical properties of a solid or a liquid. Typically such materials donot give distinctive X-ray diffraction patterns and, while exhibitingthe properties of a solid, are more formally described as a liquid. Uponheating, a change from solid to liquid properties occurs which ischaracterised by a change of state, typically second order (‘glasstransition’). The term ‘crystalline’ refers to a solid phase in whichthe material has a regular ordered internal structure at the molecularlevel and gives a distinctive X-ray diffraction pattern with definedpeaks. Such materials when heated sufficiently will also exhibit theproperties of a liquid, but the change from solid to liquid ischaracterised by a phase change, typically first order (‘meltingpoint’).

The compounds of formula (I)-(Ii) may also exist in a mesomorphic state(mesophase or liquid crystal) when subjected to suitable conditions. Themesomorphic state is intermediate between the true crystalline state andthe true liquid state (either melt or solution). Mesomorphism arising asthe result of a change in temperature is described as ‘thermotropic’ andthat resulting from the addition of a second component, such as water oranother solvent, is described as ‘lyotropic’. Compounds that have thepotential to form lyotropic mesophases are described as ‘amphiphilic’and consist of molecules which possess an ionic (such as —COO⁻Na⁺,—COO⁻K⁺, or —SO₃ ⁻N⁺) or non-ionic (such as —N⁻N⁺(CH₃)₃) polar headgroup. For more information, see Crystals and the Polarizina Microscopeby N. H. Hartshome and A. Stuart, 4^(th) Edition (Edward Arnold, 1970).

Hereinafter all references to compounds of formula (I)-(Ii) includereferences to pharmaceutically acceptable salts, solvates,multi-component complexes and liquid crystals thereof and to solvates,multi-component complexes and liquid crystals of pharmaceuticallyacceptable salts thereof.

The compounds of formula (I)-(Ii) may exhibit polymorphism and/or one ormore kinds of isomerism (e.g. optical, geometric or tautomericisomerism). The compounds of formula (I)-(Ii) may also be isotopicallylabelled. Such variation is implicit to the compounds of formula(I)-(Ii) defined as they are by reference to their structural featuresand therefore within the scope of the invention.

Compounds of formula (I)-(Ii) containing one or more asymmetric carbonatoms can exist as two or more stereoisomers. Where a compound offormula (I)-(Ii) contains an alkenyl or alkenylene group, geometriccis/trans (or Z/E) isomers are possible.

Where structural isomers are interconvertible via a low energy barrier,tautomeric isomerism (‘tautomerism’) can occur. This can take the formof proton tautomerism in compounds of formula (I)-(Ii) containing, forexample, an imino, keto, or oxime group, or so-called valencetautomerism in compounds which contain an aromatic moiety. It followsthat a single compound may exhibit more than one type of isomerism.

The pharmaceutically acceptable salts of compounds of formula (I)-(Ii)may also contain a counterion which is optically active (e.g. d-lactateor l-lysine) or racemic (e.g. dl-tartrate or dl-arginine).

Cis/trans isomers may be separated by conventional techniques well knownto those skilled in the art, for example, chromatography and fractionalcrystallization.

Conventional techniques for the preparation/isolation of individualenantiomers include chiral synthesis from a suitable optically pureprecursor or resolution of the racemate (or the racemate of a salt orderivative) using, for example, chiral high pressure liquidchromatography (HPLC). Alternatively, the racemate (or a racemicprecursor) may be reacted with a suitable optically active compound, forexample, an alcohol, or, in the case where the compound of formula(I)-(Ii) contains an acidic or basic moiety, a base or acid such as1-phenylethylamine or tartaric acid. The resulting diastereomericmixture may be separated by chromatography and/or fractionalcrystallization and one or both of the diastereoisomers converted to thecorresponding pure enantiomer(s) by means well known to a skilledperson. Chiral compounds of formula (I)-(Ii) (and chiral precursorsthereof) may be obtained in enantiomerically-enriched form usingchromatography, typically HPLC, on an asymmetric resin with a mobilephase consisting of a hydrocarbon, typically heptane or hexane,containing from 0 to 50% by volume of isopropanol, typically from 2% to20%, and from 0 to 5% by volume of an alkylamine, typically 0.1%diethylamine. Concentration of the eluate affords the enriched mixture.Chiral chromatography using sub- and supercritical fluids may beemployed. Methods for chiral chromatography useful in some embodimentsof the present invention are known in the art (see, for example, Smith,Roger M., Loughborough University, Loughborough, UK; ChromatographicScience Series (1998), 75 (Supercritical Fluid Chromatography withPacked Columns), pp. 223-249 and references cited therein). In somerelevant examples herein, columns were obtained from ChiralTechnologies, Inc, West Chester, Pa., USA, a subsidiary of Daicel®Chemical Industries, Ltd., Tokyo, Japan.

When any racemate crystallizes, crystals of two different types arepossible. The first type is the racemic compound (true racemate)referred to above wherein one homogeneous form of crystal is producedcontaining both enantiomers in equimolar amounts. The second type is theracemic mixture or conglomerate wherein two forms of crystal areproduced in equimolar amounts each comprising a single enantiomer. Whileboth of the crystal forms present in a racemic mixture have identicalphysical properties, they may have different physical propertiescompared to the true racemate. Racemic mixtures may be separated byconventional techniques known to those skilled in the art. See, forexample, Stereochemistry of Organic Compounds by E. L. Eliel and S. H.Wilen (Wiley, 1994).

The present invention includes all pharmaceutically acceptableisotopically-labelled compounds of formula (I)-(Ii) wherein one or moreatoms are replaced by atoms having the same atomic number, but an atomicmass or mass number different from the atomic mass or mass number whichpredominates in nature. Isotopically-labelled compounds of formula(I)-(Ii) can generally be prepared by conventional techniques known tothose skilled in the art or by processes analogous to those described inthe accompanying Examples and Preparations using an appropriateisotopically-labelled reagent in place of the non-labelled reagentpreviously employed. In particular, hydrogen atoms may be replaced bydeuterium atoms since such deuterated compounds are sometimes moreresistant to metabolism.

Also included within the scope of the invention are active metabolitesof compounds of formula (I)-(Ii), that is, compounds formed in vivo uponadministration of the drug, often by oxidation or dealkylation. Someexamples of metabolites in accordance with the invention include

(i) where a compound of formula (I)-(Ii) contains a methyl group, anhydroxymethyl derivative thereof (—CH₃->—CH₂OH):

(ii) where a compound of formula (I)-(Ii) contains an alkoxy group, anhydroxy derivative thereof (—OR->—OH);

(iii) where a compound of formula (I)-(Ii) contains a tertiary aminogroup, a secondary amino derivative thereof (—NRR′->—NHR or —NHR′);

(iv) where a compound of formula (I)-(Ii) contains a secondary aminogroup, a primary derivative thereof (—NHR->—NH₂);

(v) where a compound of formula (I)-(Ii) contains a phenyl moiety, aphenol derivative thereof (-Ph->-PhOH); and

-   -   (vi) where a compound of formula (I)-(Ii) contains an amide        group, a carboxylic acid derivative thereof (—CONH₂->COOH).

For administration to human patients, the total daily dose of a compoundof formula (I)-(Ii) is typically in the range of 0.01 mg to 500 mgdepending, of course, on the mode of administration. In anotherembodiment of the present invention, the total daily dose of a compoundof formula (I)-(Ii) is typically in the range of 0.1 mg to 300 mg. Inyet another embodiment of the present invention, the total daily dose ofa compound of formula (I)-(Ii) is typically in the range of 1 mg to 30mg. The total daily dose may be administered in single or divided dosesand may, at the physician's discretion, fall outside of the typicalrange given herein. These dosages are based on an average human subjecthaving a weight of about 65 kg to 70 kg. The physician will readily beable to determine doses for subjects whose weight falls outside thisrange, such as infants and the elderly.

In the case of dry powder inhalers and aerosols, the dosage unit isdetermined by means of a prefilled capsule, blister or pocket or by asystem that utilises a gravimetrically fed dosing chamber. Units inaccordance with the invention are typically arranged to administer ametered dose or “puff” containing from 1 to 5000 μg of drug. The overalldaily dose will typically be in the range 1 μg to 20 mg which may beadministered in a single dose or, more usually, as divided dosesthroughout the day.

A compound of formula (I)-(Ii) can be administered per se, or in theform of a pharmaceutical composition, which, as active constituentcontains an efficacious dose of at least one compound of the invention,in addition to customary pharmaceutically innocuous excipients and/oradditives.

Pharmaceutical compositions suitable for the delivery of compounds ofthe present invention and methods for their preparation will be readilyapparent to those skilled in the art. Such compositions and methods fortheir preparation may be found, for example, in Reminaton'sPharmaceutical Sciences, 19th Edition (Mack Publishing Company, 1995).

Compounds of formula (I)-(Ii) may be administered orally. Oraladministration may involve swallowing, so that the compound enters thegastrointestinal tract, or buccal or sublingual administration may beemployed by which the compound enters the blood stream directly from themouth. Formulations suitable for oral administration include solidformulations such as tablets, capsules containing particulates, liquids,or powders, lozenges (including liquid-filled), chews, multi- andnano-particulates, gels, solid solution, liposome, films, ovules, spraysand liquid formulations.

Liquid formulations include suspensions, solutions, syrups and elixirs.Such formulations may be employed as fillers in soft or hard capsulesand typically comprise a carrier, for example, water, ethanol,polyethylene glycol, propylene glycol, methylcellulose, or a suitableoil, and one or more emulsifying agents and/or suspending agents. Liquidformulations may also be prepared by the reconstitution of a solid, forexample, from a sachet.

Compounds of formula (I)-(Ii) may also be used in fast-dissolving,fast-disintegrating dosage forms such as those described in ExpertOpinion in Therapeutic Patents, 11 (6), 981-986, by Liang and Chen(2001).

For tablet dosage forms, depending on dose, the drug may make up from 1weight % to 80 weight % of the dosage form, more typically from 5 weight% to 60 weight % of the dosage form. In addition to the drug, tabletsgenerally contain a disintegrant. Examples of disintegrants includesodium starch glycolate, sodium carboxymethyl cellulose, calciumcarboxymethyl cellulose, croscarmellose sodium, crospovidone,polyvinylpyrrolidone, methyl cellulose, microcrystalline cellulose,lower alkyl-substituted hydroxypropyl cellulose, starch, pregelatinisedstarch and sodium alginate. Generally, the disintegrant will comprisefrom 1 weight % to 25 weight %. In one embodiment of the presentinvention, the disintegrant will comprise from 5 weight % to 20 weight %of the dosage form. Binders are generally used to impart cohesivequalities to a tablet formulation. Suitable binders includemicrocrystalline cellulose, gelatin, sugars, polyethylene glycol,natural and synthetic gums, polyvinylpyrrolidone, pregelatinised starch,hydroxypropyl cellulose and hydroxypropyl methylcellulose. Tablets mayalso contain diluents, such as lactose (monohydrate, spray-driedmonohydrate, anhydrous and the like), mannitol, xylitol, dextrose,sucrose, sorbitol, microcrystalline cellulose, starch and dibasiccalcium phosphate dihydrate. Tablets may also optionally comprisesurface active agents, such as sodium lauryl sulfate and polysorbate 80,and glidants such as silicon dioxide and talc. When present, surfaceactive agents may comprise from 0.2 weight % to 5 weight % of thetablet, and glidants may comprise from 0.2 weight % to 1 weight % of thetablet. Tablets also generally contain lubricants such as magnesiumstearate, calcium stearate, zinc stearate, sodium stearyl fumarate, andmixtures of magnesium stearate with sodium lauryl sulfate. Lubricantsgenerally comprise from 0.25 weight % to 10 weight %. In one embodimentof the present invention, lubricants comprise from 0.5 weight % to 3weight % of the tablet. Other possible ingredients includeanti-oxidants, colorants, flavoring agents, preservatives andtaste-masking agents.

Exemplary tablets contain up to about 80% drug, from about 10 weight %to about 90 weight % binder, from about 0 weight % to about 85 weight %diluent, from about 2 weight % to about 10 weight % disintegrant, andfrom about 0.25 weight % to about 10 weight % lubricant.

Tablet blends may be compressed directly or by roller to form tablets.Tablet blends or portions of blends may alternatively be wet-, dry-, ormelt-granulated, melt congealed, or extruded before tabletting. Thefinal formulation may comprise one or more layers and may be coated oruncoated; it may even be encapsulated. Formulations of tablets arediscussed in Pharmaceutical Dosage Forms: Tablets, Vol. 1, by H.Lieberman and L. Lachman (Marcel Dekker, New York, 1980).

Consumable oral films for human or veterinary use are typically pliablewater-soluble or water-swellable thin film dosage forms which may berapidly dissolving or mucoadhesive and typically comprise a compound offormula (I)-(Ii), a film-forming polymer, a binder, a solvent, ahumectant, a plasticiser, a stabiliser or emulsifier, aviscosity-modifying agent and a solvent. Some components of theformulation may perform more than one function. The film-forming polymermay be selected from natural polysaccharides, proteins, or synthetichydrocolloids and is typically present in the range 0.01 to 99 weight %,more typically in the range 30 to 80 weight %. Other possibleingredients include anti-oxidants, colorants, flavorings and flavorenhancers, preservatives, salivary stimulating agents, cooling agents,co-solvents (including oils), emollients, bulking agents, anti-foamingagents, surfactants and taste-masking agents. Films in accordance withthe invention are typically prepared by evaporative drying of thinaqueous films coated onto a peelable backing support or paper. This maybe done in a drying oven or tunnel, typically a combined coater dryer,or by freeze-drying or vacuuming.

Solid formulations for oral administration may be formulated to beimmediate and/or modified release. Modified release includes delayed,sustained, pulsed, controlled, targeted and programmed release. Suitablemodified release formulations for the purposes of the invention aredescribed in U.S. Pat. No. 6,106,864. Details of other suitable releasetechnologies such as high energy dispersions and osmotic and coatedparticles are to be found in Pharmaceutical Technology On-line, 25(2),1-14, by Verma et al (2001). The use of chewing gum to achievecontrolled release is described in WO-A-00/35298.

Compounds of formula (I)-(Ii) may also be administered directly into theblood stream, into muscle, or into an internal organ. Such parenteraladministration includes intravenous, intraarterial, intraperitoneal,intrathecal, intraventricular, intraurethral, intrasternal,intracranial, intramuscular, intra-articular and subcutaneousadministration. Suitable devices for parenteral administration includeneedle (including microneedle) injectors, needle-free injectors andinfusion techniques.

Compounds of the invention may also be administered topically to theskin or mucosa, that is, dermally or transdermally.

The compounds of formula (I)-(Ii) can also be administered intranasallyor by inhalation, typically in the form of a dry powder (either alone,as a mixture, for example, in a dry blend with lactose, or as a mixedcomponent particle, for example, mixed with phospholipids, such asphosphatidylcholine) from a dry powder inhaler, as an aerosol spray froma pressurised container, pump, spray, atomiser (preferably an atomiserusing electrohydrodynamics to produce a fine mist), or nebuliser, withor without the use of a suitable propellant, such as1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane, or asnasal drops. For intranasal use, the powder may comprise a bioadhesiveagent, for example, chitosan or cyclodextrin. Delivery by inhalation isthe preferred route of administration for the compounds of the presentinvention.

The pressurised container, pump, spray, atomizer, or nebuliser containsa solution or suspension of the compound of formula (I)-(Ii) comprising,for example, ethanol, aqueous ethanol, or a suitable alternative agentfor dispersing, solubilising, or extending release of the compound, apropellant as solvent and an optional surfactant, such as sorbitantrioleate, oleic acid, or an oligolactic acid.

Prior to use in a dry powder or suspension formulation, the drug productis micronised to a size suitable for delivery by inhalation (typicallyless than 5 microns). This may be achieved by any appropriatecomminuting method, such as spiral jet milling, fluid bed jet milling,supercritical fluid processing to form nanoparticles, high pressurehomogenisation, or spray drying.

Capsules (made, for example, from gelatin orhydroxypropylmethylcellulose), blisters and cartridges for use in aninhaler or insufflator may be formulated to contain a powder mix of thecompound of the invention, a suitable powder base such as lactose orstarch and a performance modifier such as I-leucine, mannitol, ormagnesium stearate. The lactose may be anhydrous or in the form of themonohydrate, preferably the latter. Other suitable excipients includedextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose andtrehalose.

A suitable solution formulation for use in an atomiser usingelectrohydrodynamics to produce a fine mist may contain from 1 μg to 20mg of the compound of the invention per actuation and the actuationvolume may vary from 1 μl to 1001 μl. A typical formulation may comprisea compound of formula (I)-(Ii), propylene glycol, sterile water, ethanoland sodium chloride. Alternative solvents which may be used instead ofpropylene glycol include glycerol and polyethylene glycol.

Suitable flavors, such as menthol and levomenthol, or sweeteners, suchas saccharin or saccharin sodium, may be added to those formulations ofthe invention intended for intranasal administration. Formulations forintranasal administration may be formulated to be immediate and/ormodified release using, for example, PGLA. Modified release includesdelayed, sustained, pulsed, controlled, targeted and programmed release.

Compounds of formula (I)-(Ii) may also be administered directly to theeye or ear, typically in the form of drops of a micronised suspension orsolution in isotonic, pH-adjusted, sterile saline.

Compounds of formula (I)-(Ii) may be combined with solublemacromolecular entities, such as cyclodextrin and suitable derivativesthereof or polyethylene glycol-containing polymers, in order to improvetheir solubility, dissolution rate, taste, bioavailability and/orstability when using any of the aforementioned modes of administration.Drug-cyclodextrin complexes, for example, are found to be generallyuseful for most dosage forms and administration routes. Both inclusionand non-inclusion complexes may be used. As an alternative to directcomplexation with the drug, the cyclodextrin may be used as an auxiliaryadditive, i.e. as a carrier, diluent, or solubilizer. Most commonly usedfor these purposes are alpha-, beta- and gamma-cyclodextrins, examplesof which may be found in international patent publications WO91/11172,WO94/02518 and WO98/55148.

Inasmuch as it may desirable to administer a combination of activecompounds, for example, for the purpose of treating a particular diseaseor condition, it is within the scope of the present invention that twoor more pharmaceutical compositions, at least one of which contains acompound of formula (I)-(Ii), may conveniently be combined in the formof a kit suitable for coadministration of the compositions. Thus, a kitof the invention comprises two or more separate pharmaceuticalcompositions, at least one of which contains a compound of formula(I)-(Ii), and means for separately retaining said compositions, such asa container, divided bottle, or divided foil packet. An example of sucha kit is the familiar blister pack used for the packaging of tablets,capsules and the like. Such a kit is particularly suitable foradministering different dosage forms, for example, oral and parenteral,for administering separate compositions at different dosage intervals,or for titrating the separate compositions against one another. Toassist compliance, the kit typically comprises directions foradministration and may be provided with a so-called memory aid.

The compounds of the invention may be prepared by any method known inthe art for the preparation of compounds of analogous structure. Inparticular, the compounds of the invention can be prepared by theprocedures described by reference to the Schemes that follow, or by thespecific methods described in the Examples, or by processes similar toeither.

The skilled person will appreciate that the experimental conditions setforth in the schemes that follow are illustrative of suitable conditionsfor effecting the transformations shown, and that it may be necessary ordesirable to vary the precise conditions employed for the preparation ofcompounds of formula (I)-(Ii). It will be further appreciated that itmay be necessary or desirable to carry out the transformations in adifferent order from that described in the schemes, or to modify one ormore of the transformations, to provide the desired compound of theinvention.

In addition, the skilled person will appreciate that it may be necessaryor desirable at any stage in the synthesis of compounds of the inventionto protect one or more sensitive groups, so as to prevent undesirableside reactions. In particular, it may be necessary or desirable toprotect amino or carboxylic acid groups. The protecting groups used inthe preparation of the compounds of the invention may be used inconventional manner. See, for example, those described in ‘Greene'sProtective Groups in Organic Synthesis’ by Theodora W Greene and Peter GM Wuts, third edition, (John Wiley and Sons, 1999), in particularchapters 7 (“Protection for the Amino Group”) and 5 (“Protection for theCarboxyl Group”), incorporated herein by reference, which also describesmethods for the removal of such groups.

All of the derivatives of the formula (I)-(Ii) can be prepared by theprocedures described in the general methods presented below or byroutine modifications thereof. The present invention also encompassesany one or more of these processes for preparing the derivatives offormula (I)-(Ii), in addition to any novel intermediates used therein.The person skilled in the art will appreciate that the followingreactions may be heated thermally or under microwave irradiation.

According to a first process, compounds of formula (I) may be preparedfrom compounds of formula (IX) and (VIII), as illustrated by Scheme 1.

Wherein X is —CONH—; Hal is Cl, Br or iodo; M is boronic acid orboranate ester; PG¹ is tert-butyl, 2,4-dimethoxybenzyl; PG² issilylethoxymethyl, tetrahydropyranyl; PG³ is silylethoxymethyl, benzyl,or methyl.

It may be necessary or desirable to interchange the protecting groups inthis Scheme to provide the highest yielding transformations.

Compounds of formulae (X), (IX), (VIII) and (IV) are commerciallyavailable or may be synthesized by those skilled in the art according tothe literature or preparations described herein.

Compounds of formula (I)-(II) may be prepared from compounds of formula(II) according to process step (vi), a deprotection step mediated byeither an organic acid, a Lewis acid or hydrogenation, or a sequentialcombination of each required. Preferred conditions comprise TFA and/orboron tribromide in a suitable organic solvent such as DCM or neat, atroom or elevated temperatures and/or hydrogenation using a suitablecatalyst such as 10% Pd/C in an organic solvent such as EtOH at roomtemperature.

Wherein compounds of formula (I)-(II) are racemic, chiral separation maybe employed to afford the two enantiomers. Wherein compounds of formula(I) include an R group that contains oxooxazolidine, this may be reactedwith a suitable organic base to effect an open chain R group. Preferredconditions comprise sodium hydroxide at from 0° C. to room temperaturefor 18 hours.

Compounds of formula (II) may be prepared from compounds of formula(III) according to process step (v), a carbonylation step in thepresence of a suitable amine of formula (X) or (XI), a suitablepalladium catalyst, and an organic base and a suitable solvent heatedeither in a sealed tube or under microwave irradiation. Typicalconditions comprise molybdenum hexacarbonyl with DBU and palladiumacetate heated to 100° C. either thermally for 45 minutes or undermicrowave irradiation for 10 minutes in the presence of a compound offormula (X) or (XI), such as methylamine or 88% ammonia in a suitableorganic solvent such as THF. Alternatively carbon monoxide gas(typically at 1-100 atmospheres) can be used in place of molybdenumhexacarbonyl in the carbonylation step.

Compounds of formula (III) may be prepared from compounds of formula(IV) and (V) according to process step (iv), an N-oxide rearrangementstep with compounds of formula (IV) and an organic base in a suitableorganic solvent at elevated temperatures. Preferred conditions comprisetriethylamine in DMF at elevated temperatures of between 80-100° C. for18 hours.

Compounds of formula (V) may be prepared from compounds of formula (VI)according to process step (iii), an oxidation reaction. Preferredconditions comprise mCPBA in DCM at 0° C. for 18 hours. Compounds offormula (VI) may be prepared from compounds of formula (VII) accordingto process step (ii), an electrophilic halogenation reaction. Typically,compounds (VII) have the PG² protecting group removed by methods knownto those skilled in the art prior to electrophilic halogenation.Preferred conditions comprise N-iodosuccinimide in DMF at from 0° C. toroom temperature for 18 hours followed by subsequent reprotection withPG².

Compounds of formula (VII) may be prepared from compounds of formula(IX) and (VIII) according to process step (i), a Suzuki cross-couplingreaction with compounds of formula (V). Suzuki cross-coupling isconveniently effected in the presence of a suitable catalyst, e.g.,palladium or nickel and a base. Typical conditions comprise a boronicacid or ester, a palladium catalyst with phosphine ligands in an organicsolvent at elevated temperatures. Preferred Suzuki conditions comprisepalladium acetate with phosphine ligand S-Phos, and potassium phosphatein ethanol at 80° C. for 18 hours.

According to a second process, compounds of formula (I) may be preparedfrom compounds of formula (VI) as illustrated by Scheme 2.

Wherein X is —CONH—; Hal is Cl, Br or I, PG¹ is tert-butyl,2,4-dimethoxybenzyl; PG² is silylethoxymethyl, tetrahydropyranyl; PG³ issilylethoxymethyl, benzyl, or methyl.

Compounds of formulae (XII) are commercially available or may besynthesized by those skilled in the art according to the literature orpreparations described herein. Compounds of formula (VI) are describedin Scheme 1.

Compounds of formula (I) may be prepared from compounds of formula(XIII) according to process steps (vii) and (vi), a nucleophilicaromatic substitution reaction with compounds of formula (XII) followedby a deprotection step. Typical conditions comprise heating to 90° C.with compounds of formula (XII) in a suitable organic solvent with asuitable organic base, followed by deprotection as described inScheme 1. Preferred conditions comprise DIPEA in n-butanol at 90° C. for18 hours or triethylamine in DMF at 80-100° C. for 6 hours followed byTFA in DCM followed by boron tribromide in DCM. Alternatively compoundsof formula (I) may be prepared from compounds of formula (XIII) andformula (XII) using a cross coupling reaction followed by deprotectionif required. Typical conditions comprise a suitable metal catalyst inthe presence of an inorganic base with an organic ligand. Preferredconditions comprise Pd₂(dba)₃ with BINAP and cesium carbonate in tolueneat elevated temperatures of 80-140° C. either thermally or undermicrowave irradiation.

Compounds of formula (XIII) may be prepared from compounds of formula(XIV) according to process steps (iii) and (viii), an oxidation reactionfollowed by an N-oxide rearrangement-halogenation reaction. Typicalconditions comprise oxidation as described in Scheme 1 process step(iii) followed by stirring the N-oxide in a suitable organic solvent attemperatures of 0-10° C. with electrophilic halogenating reagents.Preferred conditions comprise mCPBA in DCM followed by either POCl₃ oroxalyl chloride in DCM. Compounds of formula (XIV) may be prepared fromcompounds of formula (VI) and either (X) or (XI) according to processstep (v) as described in Scheme 1.

According to a third process, compounds of formula (I) may be preparedfrom compounds of formula (III) as illustrated by Scheme 3.

Wherein X is —CONH—; Hal is Cl, Br or I; PG¹ is tert-butyl,2,4-dimethoxybenzyl; PG² is silylethoxymethyl, tetrahydropyranyl; PG³ issilylethoxymethyl, benzyl, or methyl.

Compounds of formulae (XI) and (XI) are commercially available or may besynthesized by those skilled in the art according to the literature orpreparations described herein. Compounds of formula (III) are describedin Scheme 1. Compounds of formula (I) may be prepared from compounds offormula (II) according to process step (vi) as described in Scheme 1.Compounds of formula (II) may be prepared from compounds of formula (XV)according to process step (ix), an amide bond formation reaction withcompounds of formula (X) or (XI) with activation of the carboxylic acidvia a mixed anhydride or using a suitable base such as DIPEA and asuitable coupling agent such as HATU, BOP. Preferred conditions compriseisobutyl chloroformate in THF with NMM or BOP or HATU in DMF with DIPEAas base.

Process step (vi) may be performed before process step (ix) to obtaincompounds of formula (I) in Scheme 3.

Compounds of formula (XV) may be prepared from compounds of formula(III) according to process step (v) as described in Scheme 1 but in theabsence of compounds of formula (X) and (XI) in a solvent such asmethanol with water added if necessary.

According to a fourth process, compounds of formula (I) may be preparedfrom compounds of formula (XX) and (XIV) as illustrated by Scheme 4.

Wherein X is —CONH—; Hal is Cl, Br or I; PG¹ is tert-butyl,2,4-dimethoxybenzyl; PG² is silylethoxymethyl, tetrahydropyranyl; PG³ issilylethoxymethyl, benzyl, or methyl; PG⁴ is carboxybenzyl.

Compounds of formulae (XVII), (X) and (XI) are commercially available ormay be synthesized by those skilled in the art according to theliterature or preparations described herein. Compounds of formula (XIV)are described in Scheme 2. Compounds of formula (XXI) are described inScheme 5. Compounds of formula (I) may be prepared from compounds offormula (XVI) according to process step (vi) as described in Scheme 1.

Compounds of formula (XVI) may be prepared from compounds of formula(XVII) and (XVIII) according to process step (ix), a sulfonamideformation step. Preferred conditions comprise reacting compounds offormula (XVII) with compounds of formula (XVIII) in a suitable organicsolvent such as THF at from 0° C. to room temperature for 18 hours.Alternatively a base may be added to facilitate the reaction such assodium hydride. Compounds of formula (XVIII) may be prepared fromcompounds of formula (XIX) according to process step (vi) a deprotectionreaction as described in Scheme 1. Preferred conditions comprisepalladium on carbon in ethanol at room temperature under hydrogenationat 30 psi for 1 hour.

Compounds of formula (XIX) may be prepared from compounds of formula(XIV) according to process steps (iii) and (iv), an oxidation ofcompounds of formula (XIV) followed by a rearrangement step withcompounds of formula (XX) as described in Scheme 1.

According to a fifth process, compounds of formula (IV) may be preparedfrom compounds of formula (XXIV) as illustrated by Scheme 5.

Compounds of formulae (XXIV), (XVII) and (XXVI) are commerciallyavailable or may be synthesized by those skilled in the art according tothe literature or preparations described herein. Compounds of formula(IV) may be prepared from compounds of formula (XXI) according toprocess step (xv), a reaction to form a carbamate activating group inthe presence of an inorganic base. Preferred conditions comprise sodiumcarbonate in DCM with 4-nitrophenylchloroformate.

Compounds of formula (XXI) may be prepared from compounds of formula(XXII) according to process step (xiv), a reduction step in the presenceof a metal catalyst and an inorganic hydrogen donor or under anatmosphere of hydrogen. Preferred conditions comprise NiCl₂.6H₂O withsodium borohydride and di-tert butyl dicarbonate in methanol followed by4M HCl in dioxane or 10% palladium on carbon in acetic acid or RaneyNickel in methanolic ammonia under an atmosphere of 40 psi of hydrogenat room temperature for 18 hours.

Compounds of formula (XXII) may be prepared from compounds of formula(XXV) according to process step (xiii), an alkylation reaction withcompounds of formula (XXVI) in the presence of a quaternary ammoniumsalt. Preferred conditions comprise benzyltriethylammonium chloride and40% aqueous sodium hydroxide solution in THF with compounds of formula(XXVI). Compounds of formula (XXII) may also be prepared from compoundsof formula (XXIII) according to process step (xii), an alkylationreaction in the presence of an inorganic base. Preferred conditionscomprise potassium carbonate in acetone with compounds of formula (XXVI)or Mitsunobu conditions with compounds of formula (XVIII) using DEAD inTHF.

Compounds of formulae (XXV) and (XXIII) may be prepared from compoundsof formula (XXIV) and (XVII) according to process step (xi) asulfonamide formation reaction. Preferred conditions comprise stirringin pyridine at from 0° C. to room temperature or in the presence ofLiHMDS in THF. Compounds of formula (XXIII) may also be prepared fromsulfonamides reacting with halo-substituted heterocycles in the presenceof a base such as cesium carbonate in acetonitrile.

According to a sixth process, compounds of formula (II) may be preparedfrom compounds of formula (VII) as illustrated by Scheme 6.

Compounds of formula (VII) may be prepared as described in Scheme 1.Compounds of formulae (XII) are commercially available or may besynthesized by those skilled in the art according to the literature orpreparations described herein. Compounds of formula (I) may be preparedfrom compounds of formula (XXIX) according to reaction step (vi), adeprotection step as described in Scheme 1.

Compounds of formula (XXIX) may be prepared according to reaction step(xvi), an N-oxide rearrangement step effected by employment of adehydrating agent such as PyBrop with amines of formula (XII). Preferredconditions comprise PyBrop with DIPEA in a suitable organic solvent suchas DCM at room temperature. Alternatively the N-oxide rearrangement stepmay employ acetic anhydride to afford the hydroxy intermediate followedby interconversion to triflate. The triflate may then be converted tocompounds of formula (XXIX) by heating with amines of formula (XII).Typical conditions comprise heating the N-oxide with triethylamine andacetic anhydride, followed by triflic anhydride with pyridine in DCM atroom temperature, and finally heating with compounds of formula (XII)with triethylamine in DMF.

Compounds of formula (XXVIII) may be prepared from compounds of formula(VII) according to process step (iii) as described in Scheme 1.

According to a seventh process, compounds of formula (I) may be preparedfrom compounds of formula (VII) as illustrated by Scheme 7.

Compounds of formula (III) may be prepared as described in Scheme 1.Compounds of formulae (XXX) or (XXXI) are commercially available or maybe synthesized by those skilled in the art according to the literatureor preparations described herein.

Compounds of formula (I)-(II) may be prepared from compounds of formula(III) according to process steps (xvii) and (vi), a cross couplingreaction, such as a Stille reaction or a Buchwald reaction followed by adeprotection step if required. Typical conditions for a Stille crosscoupling reaction comprise a suitable tin reagent in the presence of oneor two metal catalysts in a suitable organic solvent at elevatedtemperatures with compounds of formula (XXX). Preferred conditionscomprise bis(tributyltin) and copper(I)iodide withtetrakis(triphenylphosphine)palladium in toluene at 100° C. Typicalconditions for a Buchwald reaction comprise a copper catalyst and asuitable organic ligand in the presence of an inorganic base at elevatedtemperatures. Preferred conditions comprise cuprous oxide and4.7-dimethoxy-1,10-phenanthroline with cesium carbonate and PEG in DMSOat 110° C.

Compounds of formula (I) may also be prepared from compounds of formula(XXXV) according to process step (xviii) a heterocyclic cyclizationreaction, either directly from the nitrile or the carboxylic acid, orvia an acyl hydrazone from the carboxylic acid. Preferred conditionscomprise heating with the required nitrile or hydrazone in butanol atelevated temperatures under microwave irradiation. Compounds of formula(XXXV) may be prepared from compounds of formula (III) according toprocess step (v) as described in Scheme 3 to afford the carboxylic acid,or using zinc cyanide and tetrakis(triphenylphosphine)palladium in DMFat elevated temperatures under microwave irradiation to afford thenitrile.

According to an eighth process, compounds of formula (I)-(II) may beprepared from compounds of formula (XXXIII) as illustrated by Scheme 8.

Wherein M is boronic acid or ester.

Compounds of formula (XXXIII) are either commercially available orprepared as described herein. Compounds of formula (I)-(I) may beprepared from compounds of formula (XXXII) and (VIII) according toprocess steps (i) and (vi), a Suzuki cross-coupling reaction followed bydeprotection as described in Scheme 1. Preferred conditions for theSuzuki step comprise PEPPSI-IPr catalyst with potassium carbonate intoluene at elevated temperatures. Compounds of formula (XXXII) may beprepared from compounds of formula (XXXIII) and (XII) according toprocess step (vii), a nucleophilc aromatic substitution reaction asdescribed in Scheme 2.

The skilled person will further appreciate that compounds of formula(I)-(II) may be interconverted to other compounds of formula (I)-(II) byfunctional group manipulation, or suitably protected compounds offormula (I)-(II) may be interconverted to other suitably protectedcompounds of formula (I)-(II) followed by a deprotection step to affordcompounds of formula (I)-(II)

Typical interconversions include:

Wherein R or R⁰ contains a ketone or aldehyde functionality, these maybe reduced using a suitable reducing agent such as sodium borohydride;

Wherein R or R⁰ contain an amine, these may be interconverted to a urea,an amide, a sulfonamide or a sulfamide followed by suitable deprotectionas required.

Wherein compounds of formula (XVI) contain an R″ group that has aleaving group such as halo, an alkylation may occur with amines such asmorpholine.

In the non-limiting Examples and Preparations that are set out later inthe description, and in the aforementioned Schemes, the following theabbreviations, definitions and analytical procedures may be referred to:

ACE-Cl is 1-chloroethylchloroformate;

BBr₃ is boron tribromide;

BINAP is 2,2′-bis(diphenylphosphino)-1,1′binapthalene;

BOP is (benzotriazol-1-yloxy)tris(dimethylamino)phosphoniumhexafluorophosphate;

Cbz is benzyloxycarbonyl;

Cs₂CO₃ is cesium carbonate;

DBU is diazabicyclo[5.4.0]undec-7-ene;

DCM is dichloromethane;

DEAD is diethylazodicarboxylate;

DIPEA is N-ethyldiisopropylamine, N,N-diisopropylethylamine;

DMAP is dimethylaminopyridine;

DMF is dimethyl formamide;

EDCl.HCl is 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride;

EtOAc is ethylacetate;

HATU is1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate;

HBTU is N,N,N′,N′-Tetramethyl-O-(1H-benzotriazol-1-yl)uroniumhexafluorophosphate;

HCl is hydrochloric acid;

HOBt is 1-hydroxybenzotriazole;

IPA is isopropanol;

KOAc is potassium acetate;

LiHMDS is lithium (bistrimethylsilyl)amide

m-CPBA is meta chloroperoxy benzoic acid

MeCN is acetonitrile;

MeOH is methanol;

NaBH₄ is sodium borohydride;

NaHCO₃ is sodium hydrogen carbonate;

NaH is sodium hydride;

NaOH is sodium hydroxide;

NBS is N-bromosuccinimide;

NiCl₂.6H₂O is nickel dichloride hydrate;

NMM is N-methylmorpholine;

NMP is N-methyl-2-pyrrolidone;

Peppsi™-IPr is[1,3-Bis(2,6-Diisopropylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II)dichloride;

Pd/C is palladium on carbon;

Pd₂(dba)₃ is tris(dibenzylideneacetone)dipalladium;

Pd(dppf)2Cl2 is1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride;

Pd(OAc)₂ is palladium acetate;

Pd(PPh₃)₄ is tetrakis(triphenylphosphine)palladium (0)

PEG is polyethylene glycol;

POCl₃ is phosphorus oxychloride;

PTSA is paratoluenesulfonic acid;

PyBrop is (benzotriazol-1-yloxy)tripyrrolidinophosphoniumhexafluorophosphate;

SEM is silylethoxymethyl;

SPhos is 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl;

TBDMS is tertbutyldimethylsilyl;

TBME is tert-butyl dimethyl ether;

t-BuOK is potassium tert-butoxide;

TEA is triethylamine;

TES is triethylsilyl;

Tf is triflate which is trifluoromethanesulfonate;

TFA is trifluoroacetic acid;

THF is tetrahydrofuran;

THP is tetrahydropyran; and,

TLC is thin layer chromatography.

¹H and ¹⁹F Nuclear magnetic resonance (NMR) spectra were in all casesconsistent with the proposed structures. Characteristic chemical shifts(δ) are given in parts-per-million downfield from tetramethylsilane (for¹H-NMR) and upfield from trichloro-fluoro-methane (for ¹⁹F NMR) usingconventional abbreviations for designation of major peaks: e.g. s,singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad.The following abbreviations have been used for common solvents: CDCl₃,deuterochloroform; d₆-DMSO, deuterodimethylsulphoxide; and CD₃OD,deuteromethanol. Where appropriate, tautomers may be recorded within theNMR data; and some exchangeable protons may not be visible. Massspectra, MS (m/z), were recorded using either electrospray ionisation(ESI) or atmospheric pressure chemical ionisation (APCI). Where relevantand unless otherwise stated the m/z data provided are for isotopes ¹⁹F,³⁵Cl, ⁷⁹Br and ¹²⁷I. Wherein preparative TLC or silica gelchromatography has been used, one skilled in the art may choose anycombination of solvents to purify the desired compound.

Either IUPAC or ACD Labs naming packages have been used, and areinterchangeably employed throughout the Examples and Preparations.

Preparative HPLC:

Where singleton compounds are purified by preparative HPLC, these aretwo methods used, shown below:

Detection for Both Analytical and Preparative QC:

Detectors: ELSD; Polymer Labs PL-ELS 2100, UV; Waters 2487 detector at225 and 255 nm

Mass Spectrometer; Waters ZQ using electrospray ionization.

Preparative Method 1 Acidic Conditions

Column: Gemini NX C18, 5 μm 21.2×100 mm; Temperature: Ambient;Detection: ELSD-MS; Mobile Phase A: 0.1% formic acid in water; MobilePhase B:

0.1% formic acid in acetonitrile; Gradient: initial 0% B, 1 min—5% B; 7mins—95% B; 9 mins—95% B; 9.1 mins—5% B; 10 mins—5% B; Flow rate: 18mL/min; Injection volume: 1000 μL

Preparative Method 2 Basic Conditions

Column: Gemini NX C18, 5 μm 21.2×100 mm; Temperature: Ambient;Detection:

ELSD-MS; Mobile Phase A: 0.1% diethylamine in water; Mobile Phase B:0.1% diethylamine in acetonitrile; Gradient: initial 0% B, 1 min—5% B; 7mins—95% B; 9 mins—95% B; 9.1 mins—5% B; 10 mins—5% B; Flow rate: 18mL/min; Injection volume: 1000 μL

Analytical LCMS QC:

-   -   Column: Gemini C18 50×4.6 mm, 3 micron; 5 minutes run.    -   Gradient initial—95% A, 5% B; 3 mins—95% B; hold to 4 mins then        back to 5% B at 4.1-5 mins. Flow rate 1.5 mL/min    -   Acidic conditions: Mobile Phase A: 0.1% Formic acid in Water.        Mobile Phase B: 0.1% Formic acid in acetonitrile    -   Basic conditions: Mobile Phase A: 0.1% ammonia in water; Mobile        Phase B: 0.1% Ammonia in acetonitrile.

Example 14-({2-[Ethyl(ethylsulfonyl)amino]benzyl}amino)-6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-N-methyl-1H-pyrazolo[4,3-c]pyridine-3-carboxamide

To a solution ofN-ethyl-N-(2-{[(6-[5-fluoro-2-(2,2,2-trifluoroethyl)-4-{[2-(trimethyl-silyl)ethoxy]methoxy}phenyl]-3-iodo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazolo[4,3-c]pyridin-4-yl)amino]methyl}phenyl)ethanesulfonamide(Preparation 62, 170 mg, 0.18 mmol) in 2M methylamine in THF (2.6 mL)was added molybdenum hexacarbonyl (48.18 mg, 0.181 mmol), DBU (82.77 ml,0.544 mmol) and palladium acetate (2.85 mg, 0.01 mmol). The reaction washeated at 100° C. under microwave irradiation for 10 minutes. Thereaction was cooled, concentrated in vacuo and purified using silica gelcolumn chromatography eluting with 30% EtOAc in hexanes. The residue wasdissolved in TFA (3 mL) and stirred at room temperature for 30 minutes.The reaction was concentrated in vacuo, dissolved in MeOH, cooled in iceand treated with ethylene diamine. The reaction was stirred at roomtemperature for 2 hours before concentrating in vacuo. The residue waspurified using silica gel column chromatography eluting with EtOAc toafford the title compound (60 mg, 58% over 2 steps).

¹H NMR (400 MHz, DMSO-d₆): δ ppm 0.90 (t, 3H), 1.15 (t, 3H), 2.85 (d,3H), 3.21 (m, 2H), 3.44-3.63 (m, 4H), 4.72-4.74 (m, 1H), 4.86-4.88 (m,1H), 6.69 (s, 1H), 6.92 (d, 1H), 7.19 (d, 1H), 7.31 (m, 2H), 7.40 (m,2H), 8.85 (m, 1H), 9.77 (m, 1H), 10.07 (s, 1H), 13.71 (s, 1H).

MS m/z 609 [M+H]⁺

The following Examples (Examples 2-25) were prepared according to themethod described for Example 1 using the appropriate pyrazolo-pyridineand Purification Method (PM) below if different from the methoddescribed:

Purification Method A: Silica gel column chromatography eluting withbetween 40-60% EtOAc in hexanes.

Purification Method B: Silica gel column chromatography or PreparativeTLC eluting with 4% MeOH in DCM.

Purification Method C: Silica gel column chromatography followed byPreparative TLC eluting both with up to 30% MeOH in DCM.

Purification Method D: Silica gel column chromatography eluting withEtOAc.

Ex Name Data 2 4-({2- MS m/z 555 [M + H]⁺ [ethyl(ethylsulfonyl)- ¹H NMR(400 MHz, DMSO-d₆): δ ppm 0.85 (t, 3H), amino]benzyl}amino)- 0.93 (t,3H), 1.20 (t, 3H), 2.84 (d, 3H), 3.15-3.31 (m, 6-(2-ethyl-5-fluoro-4-2H), 3.50-3.70 (m, 2H), 4.69-4.71 (m, 1H), 4.95-4.98 hydroxyphenyl)-N-(m, 1H), 6.62 (s, 1H), 6.74 (d, 1H), 6.97 (s, 1H), 7.31methyl-1H-pyrazolo[4,3- (m, 2H), 7.41 (m, 2H), 8.79 (m, 1H), 9.64 (m,1H). c]pyridine-3-carboxamide UsingN-ethyl-N-[2-({[6-(2-ethyl-5-fluoro-4-{[2-(trimethylsilyl)ethoxy]-methoxy}phenyl)-3-iodo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazolo[4,3-c]pyridin-4-yl]amino}-methyl)phenyl]ethanesulfonamide (Preparation 63)and PM A. 3 6-(2-ethyl-5-fluoro-4- MS m/z 541 [M + H]⁺hydroxy-phenyl)-4-({2- ¹H NMR (400 MHz, DMSO-d₆): δ ppm 0.86 (t, 3H),[(ethylsulfonyl)- 1.22 (t, 3H), 2.49 (m, 2H), 2.84 (d, 3H), 3.35 (m,2H), (methyl)amino]ben- 4.70-5.00 (br m, 2H), 6.63 (s, 1H), 6.78 (d,1H), 7.03 zyl}amino)-N-methyl- (d, 1H), 7.32 (m, 2H), 7.41 (m, 2H), 8.80(t, 1H), 9.66 1H-pyrazolo[4,3- (t, 1H), 9.76 (s, 1H), 13.63 (s, 1H).c]pyridine-3-carboxamide UsingN-[2-({[6-(2-ethyl-5-fluoro-4-{[2-)trimethyl-silyl)ethoxy]-methoxy}phenyl)-3-iodo-1-{[2-(trimethyl-silyl)ethoxy]methyl}-1H-pyrazolo[4,3-c]pyridin-4-yl]amino}methyl)phenyl]-N-methylethanesulfonamide (Preparation 64) andPM A. 4 6-(2-ethyl-5-fluoro-4- MS m/z 450 [M + H]⁺ hydroxyphenyl)-4-{[2-¹H NMR (400 MHz, DMSO-d₆): δ ppm 1.06 (t, 3H), (4-hydroxyphenyl)eth-2.66-2.84 (m, 7H), 3.62 (m, 2H), 6.61 (s, 1H), 6.65 yl]amino}-N-methyl-(m, 2H), 6.86 (m, 1H), 7.05 (m, 2H), 7.15 (m, 1H), 1H-pyrazolo[4,3- 8.73(m, 1H), 9.28 (m, 1H). c]pyridine-3-carboxamide Using4-(2-{[6-(2-ethyl-5-fluoro-4-{[2-(trimethyl-silyl)ethoxy]-methoxy}phenyl)-3-iodo-1-{[2-(trimethyl-silyl)ethoxy]methyl}-1H-pyrazolo[4,3-c]pyridin-4- yl]amino}ethyl)phenol(Preparation 65) and PM B. 5 6-(2-ethyl-5-fluoro-4- MS m/z 386 [M + H]⁺hydroxyphenyl)-N- ¹H NMR (400 MHz, DMSO-d₆): δ ppm 0.97 (d, 6H),methyl-4-[(2- 1.08 (t, 3H), 1.89 (m, 1H), 2.69 (m, 2H), 2.84 (d, 3H),methylpropyl)amino]- 3.35 (m, 2H), 6.58 (s, 1H), 6.85 (d, 1H), 7.09 (d,1H), 1H-pyrazolo[4,3- 8.74 (m, 1H), 9.31 (m, 1H), 9.79 (s, 1H), 13.50(s, 1H). c]pyridine-3-carboxamideN-ethyl-N-(2-{[(6-[5-fluoro-2-(2,2,2-trifluoroethyl)-4-{[2-(trimethylsilyl)ethoxy]methoxy}phenyl]-3-iodo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazolo[4,3-c]pyridin-4-yl)amino]methyl}phenyl)ethanesulfonamide (Preparation 66)and PM A. 6 4-({5-chloro-2- MS m/z 561 [M + H]⁺ [methyl(methyl- ¹H NMR(400 MHz, DMSO-d₆): δ ppm 0.83 (t, 3H), sulfonyl)amino]benzyl} 2.44 (m,2H), 2.86 (d, 3H), 3.05 (s, 3H), 3.08 (s, 3H), amino)-6-(2-ethyl-5-4.69-4.87 (br m, 2H), 6.66 (s, 1H), 6.78 (d, 1H), 7.03fluoro-4-hydroxyphenyl)- (d, 1H), 7.36-7.39 (m, 2H), 7.54 (d, 1H), 8.83(m, N-methyl-1H-pyrazolo[4,3- 1H), 9.69 (m, 1H), 9.77 (s, 1H), 13.67 (s,1H). c]pyridine-3-carboxamideN-[4-chloro-2-({[6-(2-ethyl-5-fluoro-4-{[2-(trimethylsilyl)ethoxy]-methoxy}phenyl)-3-iodo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazolo[4,3-c]pyridin-4-yl]amino}methyl)phenyl]-N-methylmethane- sulfonamide(Preparation 67) and PM A. 7 6-(2-ethyl-5-fluoro-4- MS m/z 545 [M + H]⁺hydroxyphenyl)-4-({5- ¹H NMR (400 MHz, DMSO-d₆): δ ppm 0.85 (t, 3H),fluoro-2-[methyl(methyl- 2.45 (br m, 2H), 2.85 (d, 3H), 3.05 (s, 3H),3.08 (s, sulfonyl)amino]benzyl} 3H), 4.69 (br m, 1H), 4.90 (br m, 1H),6.65 (s, 1H), amino)-N-methyl-1H- 6.78 (d, 1H), 7.02 (d, 1H), 7.10-7.18(m, 2H), 7.55 pyrazolo[4,3- (m, 1H), 8.83 (m, 1H), 9.68 (m, 1H), 9.77(s, 1H), c]pyridine-3-carboxamide 13.66 (s, 1H).N-[2-({[6-(2-ethyl-5-fluoro-4-{[2-(trimethylsilyl)eth-oxy]methoxy}phenyl)-3-iodo-1-{[2-(trimethylsilyl)eth-oxy]methyl}-1H-pyrazolo[4,3-c]pyridin-4-yl]amino}meth-yl)-4-fluorophenyl]-N-methylmethanesulfonamide (Preparation 68) and PMA. 8 6-(2-ethyl-5-fluoro-4- MS m/z 545 [M + H]⁺ hydroxyphenyl)-4-({2- ¹HNMR (400 MHz, DMSO-d₆): δ ppm 1.02 (t, 3H), fluoro-6-[methyl(methyl-2.66 (m, 2H), 3.02 (s, 6H), 4.57-5.00 (br m, 2H), 6.61sulfonyl)amino]benzyl} (s, 1H), 6.85 (d, 1H), 7.06 (d, 1H), 7.25 (m,1H), amino)-N-methyl-1H- 7.36-7.45 (m, 2H), 8.71 (m, 1H), 9.44 (m, 1H),9.79 pyrazolo[4,3- (s, 1H), 13.58 (s, 1H). c]pyridine-3-carboxamideN-[2-({[6-(2-ethyl-5-fluoro-4-{[2-(trimethylsilyl)eth-oxy]methoxy}phenyl)-3-iodo-1-{[2-(trimethylsilyl)eth-oxy]methyl}-1H-pyrazolo[4,3-c]pyridin-4-yl]amino}meth-yl)-3-fluorophenyl]-N-methylmethanesulfonamide (Preparation 69) and PMA. 9 6-(2-ethyl-5-fluoro-4- MS m/z 541 [M + H]⁺ hydroxyphenyl)-4-({2- ¹HNMR (400 MHz, DMSO-d₆): δ ppm 0.85 (t, 3H), [ethyl(methylsulfo- 0.93 (t,3H), 2.45 (m, 2H), 2.84 (d, 3H), 3.02 (s, 3H), nyl)amino]ben- 3.49 (m,1H), 3.68 (m, 1H), 4.70 (m, 1H), 4.97 (m, zyl}amino)-N-methyl- 1H), 6.62(s, 1H), 6.77 (d, 1H), 6.98 (d, 1H), 7.31 (m, 1H-pyrazolo[4,3- 2H(, 7.44(m, 2H), 8.79 (m, 1H), 9.63 (m, 1H), 9.73 c]pyridine-3-carboxamide (brs, 1H), 13.62 (br s, 1H).N-ethyl-N-[2-({[6-(2-ethyl-5-fluoro-4-{[2-(trimethyl-silyl)ethoxy]methoxy}phenyl)-3-iodo-1-{[2-(tri-methylsilyl)ethoxy]methyl}-1H-pyrazolo[4,3-c]pyridin-4-yl]amino}methyl)-phenyl]methanesulfonamide (Preparation 70) and PM A.10 4-[(cyclopentylmeth- MS m/z 412 [M + H]⁺ yl)amino]-6-(2-ethyl- ¹H NMR(400 MHz, DMSO-d₆): δ ppm 1.04 (t, 3H), 5-fluoro-4-hydroxy- 1.28 (m,2H), 1.54-1.61 (m, 4H), 1.77 (m, 2H), 2.15 phenyl)-N-methyl-1H- (m, 1H),2.65 (m, 2H), 2.84 (d, 3H), 3.41 (m, 2H), pyrazolo[4,3- 6.58 (s, 1H),6.85 (d, 1H), 7.12 (d, 1H), 8.73 (m, 1H), c]pyridine-3-carboxamide 9.29(m, 1H), 9.78 (s, 1H), 13.54 (br s, 1H).N-(cyclopentylmethyl)-6-(2-ethyl-5-fluoro-4-{[2-(trimethylsilyl)ethoxy]-methoxy}phenyl)-3-iodo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazolo[4,3- c]pyridin-4-amine(Preparation 71) and PM A. 11 6-[5-fluoro-4-hydroxy- MS m/z 595 [M + H]⁺2-(2,2,2-trifluoroeth- ¹H NMR (400 MHz, DMSO-d₆): δ ppm 2.21 (s, 3H),yl)phenyl]-N-methyl-4- 2.85 (d, 3H), 3.01 (s, 3H), 3.07 (s, 3H), 3.62(m, 2H), ({5-methyl-2-[meth- 4.64-4.83 (m, 2H), 6.70 (s, 1H), 6.93 (d,1H), 7.13 yl(methylsulfonyl)ami- (m, 1H), 7.19 (m, 2H), 7.37 (d, 1H),8.82 (m, 1H), no]benzyl}amino)- 9.71 (m, 1H), 10.09 (s, 1H), 13.70 (s,1H). 1H-pyrazolo[4,3- 6-(5-fluoro-2-(2,2,2-trifluoroethyl)-4-((2-c]pyridine-3-carboxamide(trimethylsilyl)ethoxy)methoxy)phenyl)-N-methyl-4-((5-methyl-2-(N-methylmethylsulfonamido)benzyl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide(Preparation 72) and PM C. 124-({2-[ethyl(methylsul- MS m/z 595 [M + H]⁺ fonyl)amino]benzyl}ami- ¹HNMR (400 MHz, DMSO-d₆): δ ppm 0.92 (t, 3H), no)-6-[5-fluoro-4- 2.85 (s,1H), 3.02 (s, 3H), 3.50 (m, 2H), 3.64 (m, hydroxy-2-(2,2,2-tri- 2H),4.72 (m, 1H), 4.93 (m, 1H), 6.69 (s, 1H), 6.93 fluoroethyl)phenyl]- (d,1H), 7.16 (d, 1H), 7.31-7.45 (m, 4H), 8.84 (m, N-methyl-1H-pyrazolo[4,3-1H), 9.75 (m, 1H), 10.07 (s, 1H), 13.70 (br s, 1H).c]pyridine-3-carboxamideN-ethyl-N-(2-{[(6-[5-fluoro-2-(2,2,2-trifluoroethyl)-4-{[2-(trimethylsilyl)ethoxy]methoxy}phenyl]-3-iodo-1-{[2-(trimethylsilyl)-ethoxy]methyl}-1H-pyrazolo[4,3-c]pyridin-4-yl)amino]methyl}-phenyl)methane sulphonamide (Preparation73) and PM D. 13 4-({2-[(ethylsulfon- MS m/z 595 [M + H]⁺yl)methyl)-amino]ben- ¹H NMR (400 MHz, DMSO-d₆): δ ppm 1.21 (t, 3H),zyl}amino)-6-[5-fluoro- 2.85 (d, 3H), 3.11 (s, 3H), 3.32 (m, 2H), 3.57(m, 4-hydroxy-2-(2,2,2- 2H), 4.72-4.84 (br m, 2H), 6.70 (s, 1H), 6.94(d, 1H), trifluoroethyl)phenyl]- 7.18-7.47 (m, 4H), 8.84 (m, 1H), 9.78(m, 1H), 10.08 N-methyl-1H-pyrazolo[4,3- (br s, 1H), 13.70 (br s, 1H).c]pyridine-3-carboxamideN-(2-{[(6-[5-fluoro-2-(2,2,2-trifluoroethyl)-4-{[2-(trimethylsilyl)-ethoxy]methoxy}phenyl]-3-iodo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazolo[4,3-c]pyridin-4-yl)amino]-methyl}phenyl)-N-methylethane Sulphonamide(Preparation 74) and PM A. 14 6-[5-fluoro-4-hydroxy- MS m/z 599 [M + H]⁺2-(2,2,2-trifluoroeth- ¹H NMR (400 MHz, DMSO-d₆): δ ppm 2.86 (d, 3H),yl)phenyl]-4-({5-fluoro- 3.05 (s, 3H), 3.08 (s, 3H), 3.55 (m, 2H),4.65-4.90 2-[methyl(methylsulfo- (m, 2H), 6.73 (s, 1H), 7.06-7.21 (m,4H), 8.86 (m, nyl)amino]benzyl}amino)- 1H), 9.80 (m, 1H), 10.10 (s, 1H),13.74 (s, 1H). N-methyl-1H-pyrazolo[4,3- UsingN-(4-fluoro-2-{[(6-[5-fluoro-2-(2,2,2-tri- c]pyridine-3-carboxamidefluoroethyl)-4-{[2-(trimethylsilyl)ethoxy]meth-oxy}phenyl]-3-iodo-1-{[2-(trimethylsilyl)eth-oxy]methyl}-1H-pyrazolo[4,3-c]pyridin-4-yl)ami-no]methyl}phenyl)-N-methylmethanesulfonamide (Preparation 75) and PM D.15 4-({5-chloro-2- MS m/z 613 [M − H]⁻ [methyl(methyl- ¹H NMR (400 MHz,DMSO-d₆): δ ppm 3.05 (d, 3H), sulfonyl)amino]benzyl} 3.05 (s, 3H), 3.07(s, 3H), 3.52 (m, 2H), 4.75-4.90 amino)-6-[5-fluoro-4- (m, 2H), 6.73 (s,1H), 6.94 (s, 1H), 7.21 (d, 1H), 7.33 hydroxy-2-(2,2,2- (m, 1H), 7.39(m, 1H), 7.54 (d, 1H), 8.86 (m, 1H), trifluoroethyl)phenyl]- 9.79 (m,1H), 10.08 (s, 1H), 13.74 (s, 1H). N-methyl-1H-pyrazolo[4,3- UsingN-(4-chloro-2-{[(6-[5-fluoro-2-(2,2,2-trifluoro-c]pyridine-3-carboxamideethyl)-4-{[2-(trimethylsilyl)ethoxy]methoxy}phenyl]-3-iodo-1-{[2-(trimethylsilyl)ethoxy]-methyl}-1H-pyrazolo[4,3-c]pyridin-4-yl)amino]methyl}phenyl)-N-methylmethanesulfonamide (Preparation 61) and PM C. 166-[5-fluoro-4-hydroxy- MS m/z 440 [M + H]⁺ 2-(2,2,2-trifluoroeth- ¹H NMR(400 MHz, DMSO-d₆): δ ppm 0.97 (s, 3H), yl)phenyl]-N-methyl-4- 0.98 (s,3H), 1.90 (m, 1H), 2.84 (d, 3H), 3.31 (m, [(2-methylpropyl)amino]- 2H),4.10 (m, 2H), 6.67 (s, 1H), 7.05 (d, 1H), 7.30 (d, 1H-pyrazolo[4,3- 1H),8.77 (m, 1H), 9.39 (m, 1H), 10.13 (s, 1H), 13.62c]pyridine-3-carboxamide (s, 1H). Using6-[5-fluoro-2-(2,2,2-trifluoroethyl)-4-{[2-(trimethylsilyl)ethoxy]-methoxy}phenyl]-3-iodo-N-(2-methylpropyl)-1-{[2-(trimethylsilyl)-ethoxy]methyl}-1H-pyrazolo[4,3-c]pyridin-4-amine (Preparation 78) and PM A. 174-[(cyclopentylmethyl)- MS m/z 466 [M + H]⁺ amino]-6-[5-fluoro-4- ¹H NMR(400 MHz, DMSO-d₆): δ ppm 1.28 (m, 2H), hydroxy-2-(2,2,2- 1.52-1.61 (m,4H), 1.79 (m, 1H), 2.15 (m, 1H), 3.39 trifluoroethyl)phenyl]- (m, 2H),4.12 (m, 2H), 6.67 (s, 1H), 7.02 (d, 1H), N-methyl-1H-pyrazolo[4,3- 7.30(d, 1H), 8.76 (m, 1H), 9.37 (m, 1H), 10.13 (s, c]pyridine-3-carboxamide1H), 13.62 (br s, 1H).N-(cyclopentylmethyl)-6-[5-fluoro-2-(2,2,2-trifluoro-ethyl)-4-{[2-(trimethylsilyl)ethoxy]methoxy}phenyl]-3-iodo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazolo[4,3-c]pyridin-4-amine (Preparation 77) and PM A. 186-[5-fluoro-4-hydroxy- MS m/z 599 [M + H]⁺ 2-(2,2,2-trifluoroeth- ¹H NMR(400 MHz, DMSO-d₆): δ ppm 2.80 (d, 3H), yl)phenyl]-4-({2-fluoro- 3.01(s, 3H), 3.02 (s, 3H), 3.80-4.25 (br m, 2H), 4.55-6-[methyl(methylsulfo- 5.10 (br m, 1H), 6.70 (s, 1H), 7.04 (d, 1H), 7.28(m, nyl)amino]benzyl}amino)- 2H), 7.43 (m, 2H), 8.74 (m, 1H), 9.54 (m,1H), 10.14 N-methyl-1H-pyrazolo[4,3- (s, 1H), 13.66 (s, 1H).c]pyridine-3-carboxamideN-(3-fluoro-2-{[(6-[5-fluoro-2-(2,2,2-trifluoroethyl)-4-{[2-(trimethylsilyl)-ethoxy]methoxy}phenyl]-3-iodo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazolo[4,3-c]pyridin-4-yl)amino]methyl}phenyl)-N-methylmethane- sulfonamide(Preparation 76) and PM A. 19 6-(2-ethyl-5-fluoro-4- MS m/z 527 [M + H]⁺hydroxy-phenyl)-N- ¹H NMR (400 MHz, DMSO-d₆): δ ppm 0.88 (t, 3H),methyl-4-({2-[meth- 2.84 (d, 3H), 3.04 (s, 3H), 3.10 (s, 3H), 3.31 (m,2H), yl(methylsulfonyl)ami- 4.69 (br m, 1H), 4.94 (br m, 1H), 6.63 (s,1H), 6.79 no]benzyl}amino)- (d, 1H), 7.04 (d, 1H), 7.30 (m, 2H), 7.42(m, 1H), 1H-pyrazolo[4,3- 7.49 (m, 1H), 8.80 (m, 1H), 9.63 (m, 1H), 9.75(s, c]pyridine-3-carboxamide 1H), 13.61 (br s, 1H).N-[2-({[6-(2-ethyl-5-fluoro-4-{[2-(trimethylsilyl)eth-oxy]methoxy}phenyl)-3-iodo-1-{[2-(trimethylsilyl)-ethoxy]methyl}-1H-pyrazolo[4,3-c]pyridin-4-yl]ami-no}methyl)phenyl]-N-methylmethanesulfonamide (Preparation 79) and PM A.20 6-[5-fluoro-4-hydroxy- MS m/z 581 [M + H]⁺ 2-(2,2,2-trifluoroeth- ¹HNMR (400 MHz, DMSO-d₆): δ ppm 2.64 (d, 3H), yl)phenyl]-N-methyl-4- 3.04(s, 3H), 3.10 (s, 3H), 3.62 (q, 2H), 4.72 (br s,({2-[methyl(methylsulfo- 1H), 4.88 (br s, 1H), 6.54 (s, 1H), 6.95 (d,1H), 7.21 nyl)amino]benzyl}amino)- (d, 1H), 7.30 (m, 2H), 7.37 (d, 1H),7.45 (m, 1H), 8.82 1H-pyrazolo[4,3- (t, 1H), 9.75 (t, 1H), 10.09 (s,1H), 13.70 (s, 1H). c]pyridine-3-carboxamideN-(2-{[(6-[5-fluoro-2-(2,2,2-trifluoroethyl)-4-{[2-(trimethylsilyl)ethoxy]-methoxy}phenyl]-3-iodo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazolo[4,3-c]pyridin-4-yl)amino]-methyl}phenyl)-N-methylmethane- sulfonamide(Preparation 105) and PM A. 21 6-(2-ethyl-5-fluoro-4- MS m/z 541 [M +H]⁺ hydroxyphenyl)-N- ¹H NMR (400 MHz, DMSO-d₆): δ ppm 0.90 (t, 3H),methyl-4-({5-methyl-2- 2.23 (s, 3H), 2.84 (d, 3H), 3.01 (s, 3H), 3.08(s, 3H), [methyl(methylsulfo- 3.39 (m, 2H), 4.65 (br m, 1H), 4.90 (br m,1H), 6.63 nyl)amino]benzyl}amino)- (s, 1H), 6.80 (d, 1H), 7.06 (d, 1H),7.14 (m, 1H), 7.23 1H-pyrazolo[4,3- (m, 1H), 7.37 (m, 1H), 8.80 (m, 1H),9.60 (m, 1H), c]pyridine-3-carboxamide 9.76 (s, 1H), 13.61 (br s, 1H).N-[2-({[6-(2-ethyl-5-fluoro-4-{[2-(trimethylsilyl)eth-oxy]methoxy}phenyl)-3-iodo-1-{[2-(trimethylsilyl)eth-oxy]-methyl}-1H-pyrazolo[4,3-c]pyridin-4-yl]amino}meth-yl)-4-methylphenyl]-N-methylmethanesulfonamide (Preparation 80) and PMA. 22 6-(2-ethyl-5-fluoro-4- MS m/z 589 [M + H]⁺ hydroxyphenyl)-N- ¹HNMR (400 MHz, DMSO-d₆): δ ppm 0.89 (t, 3H), methyl-4-({2-[meth- 3.03 (s,3H), 3.17 (d, 3H), 3.31 (m, 2H), 4.70 (br m, yl(phenylsulfonyl)ami- 1H),5.00 (br m, 1H), 6.56 (d, 1H), 6.64 (s, 1H), 6.79 no]benzyl}amino)- (d,1H), 7.05 (d, 1H), 7.16 (m, 1H), 7.28 (m, 1H), 1H-pyrazolo[4,3- 7.44 (m,1H), 7.59-7.67 (m, 4H), 7.73 (m, 1H), 8.80 c]pyridine-3-carboxamide (m,1H), 9.66 (m, 1H), 9.75 (br s, 1H), 13.62 (br s, 1H).N-[2-({[6-(2-ethyl-5-fluoro-4-{[2-(trimethylsilyl)eth-oxy]methoxy}phenyl)-3-iodo-1-{[2-(trimethylsilyl)eth-oxy]methyl}-1H-pyrazolo[4,3-c]pyridin-4-yl]amino}meth-yl)phenyl]-N-methylbenzenesulfonamide (Preparation 81) and PM B. 236-(2-ethyl-5-fluoro-4- MS m/z 589 [M + H]⁺ hydroxyphenyl)-N- ¹H NMR (400MHz, DMSO-d₆): δ ppm 1.01 (t, 3H), methyl-4-[(2-{4- 2.69 (m, 2H),2.78-2.83 (m, 5H), 3.61 (q, 2H), 6.60 [(phenylsulfonyl)-ami- (s, 1H),6.85 (d, 1H), 6.98 (m, 2H), 7.12 (m, 3H), no]phenyl}ethyl)ami- 7.48-7.57(m, 3H), 7.72 (d, 1H), 8.73 (m, 1H), 9.25 no]-1H-pyrazolo[4,3- (m, 1H),10.13 (s, 1H), 13.55 (s, 1H). c]pyridine-3-carboxamideN-[4-(2-{[6-(2-ethyl-5-fluoro-4-{[2-(trimethylsilyl)eth-oxy]methoxy}phenyl)-3-iodo-1-{[2-(trimethylsilyl)eth-oxy]methyl}-1H-pyrazolo[4,3-c]pyridin-4-yl]amino}eth-yl)phenyl]benzenesulfonamide (Preparation 82) and PM B. 246-[5-fluoro-4-hydroxy- MS m/z 611 [M + H]⁺ 2-(2,2,2-trifluoroeth- ¹H NMR(400 MHz, DMSO-d₆): δ ppm 2.85 (d, 3H), yl)phenyl]-4-({2-[(2- 3.08 (s,3H), 3.32 (m, 2H), 3.55-3.64 (m, 4H), 4.76- hydroxyethyl)-(methyl- 4.93(m, 3H), 6.70 (s, 1H), 6.93 (d, 1H), 7.21 (d, 1H), sulfonyl)amino]ben-7.30-7.36 (m, 3H), 7.46 (m, 1H), 8.84 (m, 1H), 9.73 zyl}amino)-N-methyl-(m, 1H), 10.08 (s, 1H), 13.71 (br s, 1H). 1H-pyrazolo[4,3-N-(2-{[(6-[5-fluoro-2-(2,2,2-trifluoroethyl)-4-{[2-c]pyridine-3-carboxamide(trimethylsilyl)-ethoxy]methoxy}phenyl]-3-iodo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazolo[4,3-c]pyridin-4-yl)amino]-methyl}phenyl)-N-[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]methanesulfonamide (Preparation 87) and PM B. 256-(2-ethyl-5-fluoro-4- MS m/z 557 [M + H]⁺ (Inter- hydroxyphenyl)-4-({4-¹H NMR (400 MHz, DMSO-d₆): δ ppm 0.95 (t, 3H), mediate)methoxy-2-[methyl(meth- 2.55 (m, 2H), 2.82 (d, 3H), 3.05 (s, 3H), 3.10(s, 3H), ylsulfonyl)amino]ben- 3.76 (s, 3H), 4.50-4.90 (m, 2H), 6.62 (s,1H), 6.81 (d, zyl}amino)-N-methyl- 1H), 6.92 (dd, 1H), 7.04-7.07 (m,2H), 7.34 (d, 1H), 1H-pyrazolo[4,3- 8.78 (m, 1H), 9.54 (m, 1H), 9.76 (s,1H), 13.60 (s, 1H). c]pyridine-3-carboxamide UsingN-[2-({[6-(2-ethyl-5-fluoro-4-{[2-(trimethylsilyl)ethoxy]-methoxy}phenyl)-3-iodo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazolo[4,3-c]pyridin-4-yl]amino}methyl)-5-methoxyphenyl]-N-methyl-methane- sulfonamide(Preparation 88) and PM B.

The following Examples (Examples 26-28) were prepared according to themethod described for Example 1 using ammonia in THF and the appropriatepyrazolo-pyridine and Purification Method (PM) below if different fromthe method described.

Purification Method E: Silica gel column chromatography or preparativeTLC eluting with 4% MeOH in DCM.

Example Name Data 26 6-[5-fluoro-4-hydroxy- MS m/z 629 [M + H]⁺2-(2,2,2-trifluoroeth- ¹H NMR (400 MHz, DMSO-d₆): δ ppm 3.03 (s, 3H),yl)phenyl]-4-({2-[meth- 3.70 (m, 2H), 4.68 (m, 1H), 4.92 (m, 1H), 6.60(d, yl(phenylsulfonyl)ami- 1H), 6.71 (s, 1H), 6.97 (d, 1H), 7.13-7.29(m, 3H), no]benzyl}amino)- 7.44 (d, 1H), 7.59-7.75 (m, 5H), 7.86 (br s,1H), 1H-pyrazolo[4,3- 8.21 (br s, 1H), 9.75 (m, 1H), 10.10 (s, 1H),13.69 c]pyridine-3-carboxamide (s, 1H). UsingN-(2-{[(6-[5-fluoro-2-(2,2,2-trifluoroethyl)-4-{[2-(trimethylsilyl)ethoxy]methoxy}phenyl]-3-iodo-1-{[2-(trimethylsilyl)-ethoxy]methyl}-1H-pyrazolo[4,3-c]pyridin-4-yl)amino]-methyl}phenyl)-N- methylbenzene-sulfonamide(Preparation 86). 27 6-[5-fluoro-4-hydroxy- MS m/z 596 [M + H]⁺2-(2,2,2-trifluoroeth- ¹H NMR (400 MHz, DMSO-d₆): δ ppm 3.07 (s, 3H),yl)phenyl]-4-({2-[(2- 3.32 (m, 2H), 3.56-3.67 (m, 4H), 4.73-4.92 (m,3H), hydroxyethyl)(methyl- 6.70 9s, 1H), 6.94 (d, 1H), 7.18 (d, 1H),7.21-7.45 sulfonyl)amino]benzyl} (m, 4H), 7.83 (br s, 1H), 8.19 (br s,1H), 9.74 (m, amino)-1H-pyrazolo[4,3- 1H), 10.10 (br s, 1H), 13.70 (brs, 1H). c]pyridine-3-carboxamide UsingN-(2-{[(6-[5-fluoro-2-(2,2,2-trifluoroethyl)-4-{[2-(trimethylsilyl)ethoxy]methoxy}phenyl]-3-iodo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazolo[4,3-c]pyridin-4-yl)amino]methyl}phenyl)-N-[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]methanesulfonamide (Preparation 87) and PM E. 286-(2-ethyl-5-fluoro-4- MS m/z 543 [M + H]⁺ hydroxyphenyl)-4-({4-meth- ¹HNMR (400 MHz, DMSO-d₆): δ ppm 0.95 (t, 3H), oxy-2-[methyl(methyl- 2.59(m, 2H), 3.04 (s, 3H), 3.16 (s, 3H), 3.31 (s, sulfonyl)amino]benzyl}ami-3H), 3.76 (s, 3H), 4.65 (br m, 2H), 6.62 (s, 1H), 6.79no)-1H-pyrazolo[4,3- (d, 1H), 6.91 (d, 1H), 7.04-7.07 (m, 2H), 7.34 (d,c]pyridine-3-carboxamide 1H), 7.78 (br s, 1H), 8.14 (br s, 1H), 9.53 (m,1H), 9.76 (s, 1H), 13.57 (s, 1H). UsingN-[2-({[6-(2-ethyl-5-fluoro-4-{[2-(trimethyl-silyl)ethoxy]methoxy}phenyl)-3-iodo-1-{[2-(trimethyl-silyl)-ethoxy]methyl}-1H-pyrazolo[4,3-c]pyridin-4-yl]amino}methyl)-5-methoxyphenyl]-N-methylmethane- sulfonamide(Preparation 88) and PM E.

Example 29

6-(2-Ethyl-5-fluoro-4-hydroxyphenyl)-4-({4-hydroxy-2-[methyl(methylsulfonyl)amino]benzyl}amino)-N-methyl-1H-pyrazolo[4,3-c]pyridine-3-carboxamide

To a solution of6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-4-({4-methoxy-2-[methyl(methyl-sulfonyl)amino]benzyl}amino)-N-methyl-1H-pyrazolo[4,3-c]pyridine-3-carboxamide(Example 28, 80 mg, 0.14 mmol) in DCM (10 mL) was added boron tribromide(0.09 mL, 1 mmol) at 0° C. The reaction was stirred at room temperaturefor 2 hours before the addition of further boron tribromide (0.09 mL, 1mmol) and further stirring for 2 hours. The reaction was partitionedbetween DCM and saturated aqueous sodium bicarbonate solution, theorganic layer was collected, dried over sodium sulfate and concentratedin vacuo. The residue was purified using Preparative HPLC to afford thetitle compound (32 mg, 41%). ¹H NMR (400 MHz, DMSO-d₆): δ ppm 0.94 (t,3H), 2.59 (m, 2H), 2.81 (d, 3H), 3.02 (s, 3H), 3.07 (s, 3H), 4.69 (br m,2H), 6.61 (s, 1H), 6.73 (dd, 1H), 6.79-6.83 (m, 2H), 7.05 (d, 1H), 7.23(d, 1H), 8.76 (m, 1H), 9.49 (m, 1H), 9.60 (br s, 1H). MS m/z 543 [M+H]⁺

Example 306-(2-Ethyl-5-fluoro-4-hydroxyphenyl)-4-({4-hydroxy-2-[methyl(methylsulfonyl)amino]benzyl}amino)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide

The title compound was prepared according to the method described forExample 29 using6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-4-({4-methoxy-2-[methyl(methylsulfonyl)amino]-benzyl}amino)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide(Example 27). ¹H NMR (400 MHz, DMSO-d₆): δ ppm 0.96 (t, 3H), 2.60 (m,2H), 3.01 (s, 3H), 3.08 (s, 3H), 4.65 (br m, 2H), 6.61 (s, 1H), 6.74(dd, 1H), 6.80-6.83 (m, 2H), 7.09 (d, 1H), 7.25 (d, 1H), 7.77 (br s,1H), 8.13 (br s, 1H), 9.49 (m, 1H), 9.56 (s, 1H), 9.76 (s, 1H), 13.56(s, 1H). MS m/z 529 [M+H]⁺

Example 31 6-(2-Ethyl-5-fluoro-4-hydroxyphenyl)-4-({5-hydroxy-2-[methyl(methylsulfonyl)amino]benzyl}amino)-N-methyl-1H-pyrazolo[4,3-c]pyridine-3-carboxamide

To a solution ofN-[2-({[6-(2-ethyl-5-fluoro-4-{[2-(trimethylsilyl)-ethoxy]meth-oxy}phenyl)-3-iodo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazolo[4,3-c]-pyridin-4-yl]-amino}methyl)-4-methoxyphenyl]-N-methylmethanesulfonamide(Preparation 83, 250 mg, 0.28 mmol) in 2M methylamine in THF (3 mL) wasadded DBU (0.13 mL, 0.85 mmol), palladium acetate (4.43 mg, 0.02 mmol)and molybdenum hexacarbonyl (75 mg, 0.28 mmol) and the reaction washeated to 100° C. for 10 minutes under microwave irradiation. Thereaction was cooled, concentrated in vacuo and purified directly usingsilica gel column chromatography eluting with 45% EtOAc in hexanes. Theresulting oil was dissolved in DCM (15 mL) and cooled to 0° C. BBr₃(0.10 mL, 1.07 mmol) was added and the reaction stirred at roomtemperature for 6 hours. The reaction was concentrated in vacuo andpartitioned between saturated aqueous sodium bicarbonate solution andEtOAc. The organic layer was collected, dried over sodium sulfate andconcentrated in vacuo. The residue was purified using preparative TLCeluting with 5% MeOH in DCM to afford the title compound as a whitesolid (43 mg, 27% over two steps). ¹H NMR (400 MHz, DMSO-d₆): δ ppm 0.88(t, 3H), 2.84 (d, 3H), 2.98 (s, 3H), 3.05 (s, 3H), 3.31 (m, 2H), 4.61(m, 1H), 4.86 (m, 1H), 6.66 (m, 2H), 6.78 (m, 2H), 7.05 (d, 1H), 7.26(d, 1H), 8.80 (m, 1H), 9.51 (s, 1H), 9.59 (m, 1H), 9.74 (s, 1H), 13.62(s, 1H). MS m/z 543 [M+H]⁺

Example 326-[5-Fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-4-[(2-{[(3-hydroxyphenyl)sulfonyl](methyl)amino}benzyl)amino]-N-methyl-1H-pyrazolo[4,3-c]pyridine-3-carboxamide

To a solution ofN-(2-{[(6-[5-fluoro-4-methoxy-2-(2,2,2-trifluoroethyl)phenyl]-3-iodo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazolo[4,3-c]pyridin-4-yl)amino]methyl}-phenyl)-3-methoxy-N-methylbenzenesulfonamide(Preparation 106, 330 mg, 0.37 mmol) in 2M methylamine in THF (2 mL) wasadded DBU (0.16 mL, 1.19 mmol), palladium acetate (5.86 mg, 0.03 mmol)and molybdenum hexacarbonyl (99 mg, 0.37 mmol) and the reaction washeated to 100° C. for 10 minutes under microwave irradiation. Thereaction was cooled, concentrated in vacuo and purified using silica gelcolumn chromatography eluting with 35% EtOAc in hexanes. The resultingoil was treated with TFA (0.5 mL) and the solution stirred at roomtemperature for 30 minutes before concentrating in vacuo. Ethylenediamine (0.5 mL) was added and the reaction stirred at room temperaturefor 15 minutes before pouring onto ice-water and extracting into 20% IPAin DCM. The organic layer was collected, dried over sodium sulfate andconcentrated in vacuo. The residue was purified using silica gel columnchromatography eluting with 45% EtOAc in hexanes. The residue wasdissolved in DCM (10 mL) and boron tribromide (0.18 mL, 1.89 mmol) wasadded dropwise at 0° C. The reaction was stirred at room temperature for2 hours followed by quenching with saturated aqueous sodium bicarbonatesolution and extracting into 20% IPA in DCM. The organic layer wascollected, dried over sodium sulfate and concentrated in vacuo. Theresidue was purified using silica gel column chromatography followed bypreparative TLC eluting both with 57% EtOAc in hexanes to afford thetitle compound as a yellow solid (25 mg, 10% over 3 steps).

¹H NMR (400 MHz, DMSO-d₆): δ ppm 2.85 (d, 3H), 3.01 (s, 3H), 3.59-3.65(m, 2H), 4.71 (m, 1H), 4.95 (m, 1H), 6.63 (d, 1H), 6.71 (s, 1H), 6.96(d, 1H), 7.02 (m, 1H), 7.09 (m, 2H), 7.14-7.29 (m, 3H), 7.41 (m, 2H),8.86 (m, 1H), 9.78 (m, 1H), 10.10 (s, 1H), 10.15 (s, 1H), 13.71 (s, 1H).MS m/z 659 [M+H]⁺

The following Examples (Examples 33-37) were prepared according to themethod described for Example 32 using the appropriate pyrazolo-pyridine,and Purification Method (PM) below if different from the methoddescribed:

Purification Method F: Silica gel column chromatography or preparativeTLC eluting with 4% MeOH in DCM.

Ex Name Data 33 6-[5-fluoro-4-hydroxy- MS m/z 597 [M + H]⁺2-(2,2,2-trifluoroeth- ¹H NMR (400 MHz, DMSO-d₆): δ ppm 2.83 (d, 3H),yl)phenyl]-4-({4-hydroxy- 3.02 (s, 3H), 3.17 (s, 3H), 3.77 (m, 2H), 4.70(br m, 2-[methyl(methylsulfo- 2H), 6.69-6.73 (m, 2H), 6.83 (m, 1H), 6.97(m, 1H), nyl)amino]benzyl}amino)- 7.20-7.25 (m, 2H), 8.80 (m, 1H), 9.56(s, 1H), 9.60 N-methyl-1H-pyrazolo[4,3- (m, 1H), 10.10 (s, 1H), 13.67(s, 1H). c]pyridine-3-carboxamide UsingN-(2-{[(6-[5-fluoro-2-(2,2,2-trifluoroethyl)-4-{[2-(trimethylsilyl)-ethoxy]methoxy}phenyl]-3-iodo-1-{[2-(trimethylsilyl)-ethoxy]methyl}-1H-pyrazolo[4,3-c]pyridin-4-yl)amino]methyl}-5-methoxyphenyl)-N-methylmethane-sulfonamide (Preparation 89). 34 4-({2-[ethyl(methyl- MSm/z 611 [M + H]⁺ sulfonyl)amino]-5- ¹H NMR (400 MHz, DMSO-d₆): δ ppm0.90 (t, 3H), hydroxybenzyl}amino)- 2.88 (d, 3H), 2.96 (s, 3H),3.39-3.51 (m, 2H), 3.54- 6-[5-fluoro-4-hydroxy- 3.68 (m, 2H), 4.60 (m,1H), 4.80 (m, 1H), 6.66 (m, 2-(2,2,2-trifluoroeth- 1H), 6.69 (s, 1H),6.78 (s, 1H), 6.93 (d, 1H), 7.20 yl)phenyl]-N-methyl- (m, 2H), 7.95 (brs, 1H), 8.85 (m, 1H), 9.50 (s, 1H), 1H-pyrazolo[4,3- 9.70 (m, 1H), 10.07(br s, 1H), 13.71 (br s, 1H). c]pyridine-3-carboxamide UsingN-ethyl-N-(2-{[(6-[5-fluoro-4-methoxy-2-(2,2,2-trifluoroethyl)phenyl]-3-iodo-1-{[2-(trimethyl-silyl)ethoxy]methyl}-1H-pyrazolo[4,3-c]pyridin-4-yl)amino]methyl}-4-methoxyphenyl)methanesulfonamide (Preparation 107).35 6-[5-fluoro-4-hydroxy- MS m/z 659 [M + H]⁺ 2-(2,2,2-trifluoroeth- ¹HNMR (400 MHz, DMSO-d₆): δ ppm 2.86 (d, 3H), yl)phenyl]-4-({5-hydroxy-2.97 (s, 3H), 3.63 (m, 2H), 4.58 (m, 1H), 4.86 (m,2-[methyl(phenylsulfo- 1H), 6.34 (m, 1H), 6.47 (m, 1H), 6.71 (s, 1H),6.77 nyl)amino]benzyl}amino)- (s, 1H), 6.93 (d, 1H), 7.23 (d, 1H),7.58-7.73 (m, N-methyl-1H-pyrazolo[4,3- 5H), 8.85 (m, 1H), 9.51 (s, 1H),9.71 (m, 1H), 10.07 c]pyridine-3-carboxamide (s, 1H), 13.70 (s, 1H).Using N-(2-{[(6-[5-fluoro-4-methoxy-2-(2,2,2-trifluoroethyl)phenyl]-3-iodo-1-{[2-(trimethyl-silyl)ethoxy]-methyl}-1H-pyrazolo[4,3-c]pyridin-4-yl)amino]methyl}-4-methoxy-phenyl)-N-methyl- benzene-sulfonamide(Preparation 108). 36 4-({2-[ethyl(phenyl- MS m/z 673 [M + H]⁺sulfonyl)amino]-5- ¹H NMR (400 MHz, DMSO-d₆): δ ppm 0.85 (t, 3H),hydroxybenzyl}amino)- 2.86 (d, 3H), 3.22 (m, 1H), 3.53 (m, 1H), 3.68 (m,6-[5-fluoro-4-hydroxy- 2H), 4.52 (m, 1H), 4.81 (m, 1H), 6.41 (d, 1H),6.48 2-(2,2,2-trifluoroeth- (dd, 1H), 6.70 (s, 1H), 6.78 (d, 1H), 6.94(d, 1H), yl)phenyl]-N-methyl- 7.21 (d, 1H), 7.56-7.70 (m, 5H), 8.83 (m,1H), 9.52 1H-pyrazolo[4,3- (s, 1H), 9.67 (m, 1H), 10.06 (s, 1H), 13.71(s, 1H). c]pyridine-3-carboxamide UsingN-ethyl-N-(2-{[(6-[5-fluoro-2-(2,2,2-trifluoro-ethyl)-4-{[2-(trimethylsilyl)ethoxy]methoxy}phenyl]-3-iodo-1-{[2-(trimethylsilyl)ethoxy]-methyl}-1H-pyrazolo[4,3-c]pyridin-4-yl)amino]methyl}-4-methoxyphenyl)benzenesulfonamide (Preparation 90). 376-(2-cyclopropyl-5- MS m/z 538 [M + H]⁺ fluoro-4-hydroxyphenyl)- ¹H NMR(400 MHz, DMSO-d₆): δ ppm 0.45 (m, 2H), N-methyl-4-({2-[meth- 0.61 (m,2H), 2.09 (m, 1H), 2.84 (s, 3H), 3.06 (s, yl(methylsulfonyl)ami- 3H),3.14 (s, 3H), 4.70 (br m, 1H), 5.00 (br m, 1H), no]benzyl}amino)- 6.46(m, 1H), 6.79 (s, 1H), 7.70 (m, 1H), 7.31 (m, 1H-pyrazolo[4,3- 2H), 7.41(m, 1H), 7.50 (m, 1H), 8.78 (m, 1H), 9.62 c]pyridine-3-carboxamide (m,1H), 9.73 (m, 1H), 13.61 (m, 1H). UsingN-[2-({[6-(2-cyclopropyl-5-fluoro-4-methoxy-phenyl)-3-iodo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazolo[4,3-c]pyridin-4-yl]amino}methyl)phenyl]-N-methylmethanesulfonamide (Preparation 109) and PM F.

Examples 38 and 396-(2-Ethyl-5-fluoro-4-hydroxyphenyl)-N-methyl-4-{[(1R)-1-{2-[methyl(methylsulfonyl)amino]phenyl}ethyl]amino}-1H-pyrazolo[4,3-c]pyridine-3-carboxamideand6-(2-Ethyl-5-fluoro-4-hydroxyphenyl)-N-methyl-4-{[(1S)-1-{2-[methyl(methylsulfonyl)amino]phenyl}ethyl]amino}-1H-pyrazolo[4,3-c]pyridine-3-carboxamide

The title compounds were prepared according to the method described forExample 1 using racemicN-[2-(1-([6-(2-ethyl-5-fluoro-4-{[2-(trimethylsilyl)ethoxy]-methoxy}phenyl)-3-iodo-1-{[2-(trimethyl-silyl)ethoxy]methyl}-1H-pyrazolo[4,3-c]pyridin-4-yl]amino)ethyl)phenyl]-N-methylmethanesulfonamide(Preparation 84). The residue was purified using silica gel columnchromatography eluting with 6% MeOH in DCM followed by chiral separationusing chiral preparative HPLC to afford the separated enantiomers.

Fraction 1: 44 mg, 100% ee, registered as (R)—enantiomer Example 38

¹H NMR (400 MHz, DMSO-d₆): δ ppm 0.86 (t, 3H), 1.53 (d, 3H), 2.21 (m,2H), 2.83 (s, 3H), 2.90 (d, 3H), 3.08 (s, 3H), 5.47 (m, 1H), 6.50 (s,1H), 6.73 (m, 2H), 7.21-7.45 (m, 4H), 8.82 (m, 1H), 9.69 (br s, 1H),9.86 (m, 1H), 13.57 (br s, 1H). MS m/z 541 [M+H]⁺

Fraction 2: 41 mg, 87.5% ee, registered as (S)—enantiomer Example 39

¹H NMR (400 MHz, DMSO-d₆): δ ppm 0.86 (t, 3H), 1.53 (d, 3H), 2.21 (m,2H), 2.83 (s, 3H), 2.90 (d, 3H), 3.08 (s, 3H), 5.47 (m, 1H), 6.50 (s,1H), 6.73 (m, 2H), 7.21-7.45 (m, 4H), 8.82 (m, 1H), 9.69 (br s, 1H),9.86 (m, 1H), 13.57 (br s, 1H). MS m/z 541 [M+H]⁺

Example 406-(2-Ethyl-5-fluoro-4-hydroxyphenyl)-4-({2-[methyl(phenylsulfonyl)amino]benzyl}amino)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide

To a solution ofN-[2-({[6-(2-ethyl-5-fluoro-4-{[2-(trimethylsilyl)ethoxy]-methoxy}phenyl)-3-iodo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazolo[4,3-c]pyridin-4-yl]amino}methyl)phenyl]-N-methylbenzenesulfonamide(Preparation 81, 400 mg, 0.44 mmol) in MeOH (2 mL) was added DBU (0.20mL, 1.31 mmol), palladium acetate (6.85 mg, 0.03 mmol) and molybdenumhexacarbonyl (115 mg, 0.44 mmol) and the reaction was heated to 125° C.under microwave irradiation for 20 minutes. The reaction was cooled,concentrated in vacuo and purified using silica gel columnchromatography eluting with 70% EtOAc in hexanes. The residue wasdissolved in THF (4 mL) and cooled to −20° C. NMM (0.021 mL, 0.19 mmol)followed by isobutylchloroformate (0.03 mL, 0.19 mmol) were added andthe reaction stirred at this temperature for 2 hours. Aqueous ammoniawas then added and the reaction stirred at room temperature for 1 hour.The reaction was quenched by the addition of water and extracted intoEtOAc. The organic layer was collected, dried over sodium sulfate andconcentrated in vacuo. The residue was purified using silica gel columnchromatography eluting with 40% EtOAc in hexanes. The residue wastreated with TFA (2 mL) and stirred for 2 hours before concentrating invacuo. Ethylene diamine (0.5 mL) was added and the reaction stirred atroom temperature for 1 hour before concentrating in vacuo, pouring ontoice-water and extracting into EtOAc. The organic layer was collected,dried over sodium sulfate and concentrated in vacuo. The residue waspurified using Preparative TLC eluting with 60% EtOAc in hexanes toafford the title compound (23 mg, 10% over 3 steps).

¹H NMR (400 MHz, DMSO-d₆): δ ppm 0.92 (t, 3H), 3.04 (s, 3H), 3.40 (m,2H), 4.70 (br m, 1H), 5.00 (br m, 1H), 6.55 (d, 1H), 6.64 (s, 1H), 6.80(d, 1H), 7.06 (m, 1H), 7.14 (m, 1H), 7.29 (m, 1H), 7.47 (m, 1H),7.59-7.67 (m, 4H), 7.73 (m, 1H), 7.83 (br s, 1H), 8.18 (br s, 1H), 9.65(m, 1H), 9.77 (s, 1H), 13.60 (br s, 1H). MS m/z 575 [M+H]⁺

Example 416-[5-Fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-4-({4-hydroxy-2-[methyl(methylsulfonyl)amino]benzyl}amino)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide

A solution of6-[5-fluoro-2-(2,2,2-trifluoroethyl)-4-{[2-(trimethyl-silyl)ethoxy]methoxy}phenyl]-4-({4-methoxy-2-[methyl(methylsulfonyl)amino]-benzyl}-amino)-1-{[2-(trimethylsilyl)ethoxy]-methyl}-1H-pyrazolo[4,3-c]pyridine-3-carboxamide(Preparation 21, 102 mg, 0.15 mmol) in TFA (5 mL) was stirred at roomtemperature for 30 minutes before concentrating in vacuo. Ethylenediamine (0.5 mL) was added and the reaction stirred at room temperaturefor 15 minutes before concentrating in vacuo, pouring onto ice-water andextracting into EtOAc. The organic layer was collected, dried oversodium sulfate and concentrated in vacuo. The residue was purified usingpreparative TLC to afford a white solid. The solid was dissolved in DCM(5 mL) and boron tribromide (0.108 mL, 1.14 mmol) was added dropwise at0° C. and stirred at room temperature for 2 hours. The reaction waswashed with saturated aqueous sodium bicarbonate solution, the organiclayer collected, washed with brine, dried over sodium sulfate andconcentrated in vacuo. The residue was purified using preparative TLCeluting with 5% MeOH in DCM to afford the title compound (37 mg, 54%).¹H NMR (400 MHz, DMSO-d₆): δ ppm 3.02 (s, 3H), 3.08 (s, 3H), 3.79 (m,2H), 4.65 (br m, 2H), 6.69-6.73 (m, 2H), 6.83 (m, 1H), 6.99 (d, 1H),7.20-7.25 (m, 2H), 7.81 (s, 1H), 8.17 (s, 1H), 9.59 (m, 2H), 10.10 (brs, 1H), 13.70 (br s, 1H). MS m/z 583 [M+H]⁺

The following Examples (Examples 42-54) were prepared according to themethod described for Example 41 using the appropriate pyrazolo-pyridine,and Purification Method (PM) as described below if different from themethod described:

Purification Method G: Silica gel column chromatography eluting with5-7% MeOH in DCM followed by preparative HPLC.

Ex Name Data 42 6-[5-fluoro-4-hydroxy- MS m/z 645 [M + H]⁺2-(2,2,2-trifluoroeth- ¹H NMR (400 MHz, DMSO-d₆): δ ppm 2.98 (s, 3H),yl)phenyl]-4-({5-hydroxy- 3.69 (m, 2H), 4.57 (m, 1H), 4.83 (m, 1H), 6.35(m, 2-[methyl(phenylsulfonyl)- 1H), 6.47 (m, 1H), 6.71 (s, 1H), 6.79 (d,1H), 6.96 amino]benzyl}amino)- (d, 1H), 7.24 (d, 1H), 7.58-7.73 (m, 5H),7.87 (br s, 1H-pyrazolo[4,3- 1H), 8.22 (br s, 1H), 9.53 (s, 1H), 9.71(m, 1H), c]pyridine-3-carboxamide 10.09 (s, 1H), 13.69 (s, 1H). Using6-[5-fluoro-4-methoxy-2-(2,2,2-trifluoroeth-yl)phenyl]-4-({5-methoxy-2-[methyl(phenylsulfonyl)ami-no]benzyl}amino)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazolo[4,3-c]pyridine-3-carboxamide (Preparation 24). 434-({2-[ethyl(phenyl- MS m/z 657 [M − H]⁻ sulfonyl)amino]-5- ¹H NMR (400MHz, DMSO-d₆): δ ppm 0.85 (t, 3H), hydroxybenzyl}amino)- 3.23 (m, 1H),3.67 (m, 1H), 3.70 (m, 2H), 4.50 (m, 6-[5-fluoro-4-hydroxy- 1H), 4.79(m, 1H), 6.40 (m, 1H), 6.50 (m, 1H), 6.70 2-(2,2,2-trifluoroethyl)- (s,1H), 6.80 (s, 1H), 6.95 (d, 1H), 7.22 (d, 1H), phenyl]-1H-pyrazolo[4,3-7.55-7.68 (m, 5H), 7.85 (br s, 1H), 8.20 (br s, 1H),c]pyridine-3-carboxamide 9.52 (s, 1H), 9.68 (m, 1H), 10.05 (s, 1H),13.67 (br s, 1H). Using N-ethyl-N-(2-{[(6-[5-fluoro-2-(2,2,2-trifluoro-ethyl)-4-{[2-(trimethylsilyl)ethoxy]methoxy}phenyl]-3-iodo-1-{[2-(trimethylsilyl)-ethoxy]methyl}-1H-pyrazolo[4,3-c]pyridin-4-yl)amino]methyl}-4-methoxy-phenyl)benzenesulfonamide (Preparation 25). 44 6-[5-fluoro-4-hydroxy- MSm/z 645 [M + H]⁺ 2-(2,2,2-trifluoroeth- ¹H NMR (400 MHz, DMSO-d₆): δ ppm2.87 (m, 6H), yl)phenyl]-N-methyl-4- 3.62 (m, 2H), 5.06 (m, 2H), 6.68(s, 1H), 6.97 (d, [({3-[methyl(phenyl- 1H), 7.15 (d, 1H), 7.61 (m, 4H),7.73 (m, 1H), 8.33 sulfonyl)amino]pyrazin-2- (s, 1H), 8.58 (s, 1H), 8.78(m, 1H), 9.89 (m, 1H), yl}methyl)amino]- 10.08 (s, 1H), 13.67 (s, 1H).1H-pyrazolo[4,3- Using 6-[5-fluoro-4-methoxy-2-(2,2,2-trifluoroeth-c]pyridine-3-carboxamideyl)phenyl]-N-methyl-4-[({3-[methyl(phenylsulfonyl)ami-no]pyrazin-2-yl}methyl)amino]-1-{[2-(trimethylsilyl)eth-oxy]methyl}-1H-pyrazolo[4,3-c]pyridine-3-carboxamide (Preparation 39).45 4-[({3-[ethyl(methyl- MS m/z 597 [M + H]⁺ sulfonyl)-amino]pyrazin- ¹HNMR (400 MHz, DMSO-d₆): δ ppm 0.85 (t, 3H), 2-yl}methyl)amino]-6- 2.85(d, 3H), 3.10 (s, 3H), 3.49 (q, 2H), 3.69 (q, 2H),[5-fluoro-4-hydroxy-2- 4.99 (m, 2H), 6.68 (s, 1H), 6.95 (d, 1H), 7.10(d, (2,2,2-trifluoroeth- 1H), 8.54 (s, 1H), 8.61 (s, 1H), 8.79 (m, 1H),9.82 yl)phenyl]-N-methyl- (m, 1H), 10.07 (s, 1H), 13.67 (s, 1H).1H-pyrazolo[4,3- Using 4-[({3-[ethyl(methylsulfonyl)amino]pyrazin-2-c]pyridine-3-carboxamideyl}methyl)amino]-6-[5-fluoro-4-methoxy-2-(2,2,2-trifluoroethyl)phenyl]-N-methyl-1-{[2-(trimethyl-silyl)ethoxy]methyl}-1H-pyrazolo[4,3-c]pyridine-3- carboxamide(Preparation 40) and PM G. 46 N-ethyl-4-[({3-[eth- MS m/z 611 [M + H]⁺yl(methylsulfonyl)ami- ¹H NMR (400 MHz, DMSO-d₆): δ ppm 0.86 (t, 3H),no]pyrazin-2-yl}meth- 1.14 (t, 3H), 3.35 (m, 2H), 3.53 (m, 2H), 3.67 (m,yl)amino]-6-[5-fluoro- 2H), 4.99 (m, 2H), 6.68 (s, 1H), 6.94 (d, 1H),7.13 4-hydroxy-2-(2,2,2- (d, 1H), 8.54 (s, 1H), 8.60 (s, 1H), 8.83 (m,1H), trifluoroethyl)phenyl]- 9.81 (m, 1H), 10.07 (s, 1H), 13.68 (s, 1H).1H-pyrazolo[4,3- Using N-ethyl-4-[({3-[ethyl(methylsulfonyl)ami-c]pyridine-3-carboxamideno]pyrazin-2-yl}methyl)amino]-6-[5-fluoro-4-methoxy-2-(2,2,2-trifluoroethyl)phenyl]-1-{[2-(trimethyl-silyl)ethoxy]methyl}-1H-pyrazolo[4,3-c]pyridine-3- carboxamide(Preparation 41). 47 6-(2-cyclopropyl-5- MS m/z 525 [M + H]⁺fluoro-4-hydroxyphenyl)- ¹H NMR (400 MHz, DMSO-d₆): δ ppm 0.46 (m, 2H),4-({2-[methyl(methylsul- 0.65 (m, 2H), 2.09 (m, 1H), 3.05 (s, 3H), 3.14(s, fonyl)amino]benzyl}ami- 3H), 4.70 (br m, 1H), 5.00 (br m, 1H), 6.45(d, 1H), no)-1H-pyrazolo[4,3- 6.80 (s, 1H), 7.09 (d, 1H), 7.32 (m, 2H),7.45 (m, c]pyridine-3-carboxamide 2H), 7.81 (s, 1H), 8.16 (s, 1H), 9.62(m, 1H), 9.73 (s, 1H), 13.59 (br s, 1H). Using6-(2-cyclopropyl-5-fluoro-4-methoxyphenyl)-4-({2-[methyl(methylsulfonyl)amino]benzyl}amino)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazolo[4,3-c]pyridine-3-carboxamide (Preparation 26) and PM G. 486-[5-fluoro-4-hydroxy- MS m/z 582 [M + H]⁺ 2-(2,2,2-trifluoroeth- ¹H NMR(400 MHz, DMSO-d₆): δ ppm 2.83 (s, 3H), yl)phenyl]-N-methyl-4- 2.90 (s,3H), 3.70 (s, 3H), 3.85 (m, 2H), 4.47 (m, [({4-[methyl(methyl- 2H), 6.72(s, 1H), 7.00 (d, 1H), 7.20-7.26 (m, 2H), sulfonyl)amino]pyridin-3- 7.77(s, 1H), 7.87 (m, 1H), 8.78 (m, 1H), 9.67 (m, yl}methyl)amino]- 1H),10.13 (s, 1H), 13.67 (s, 1H). 1H-pyrazolo[4,3- Using6-[5-fluoro-4-methoxy-2-(2,2,2-trifluoroeth- c]pyridine-3-carboxamideyl)phenyl]-N-methyl-4-[({4-[methyl(methylsulfonyl)ami-no]pyridin-3-yl}methyl)amino]-1-{[2-(trimethylsilyl)eth-oxy]methyl}-1H-pyrazolo[4,3-c]pyridine-3-carboxamide (Preparation 42).49 6-(2-cyclopropyl-5- MS m/z 540 [M + H]⁺ fluoro-4-hydroxyphenyl)- ¹HNMR (400 MHz, DMSO-d₆): δ ppm 0.45 (m, 2H), N-methyl-4-[({2- 0.61 (m,2H), 2.00 (m, 1H), 2.84 (d, 3H), 3.11 (s, [methyl(methylsulfonyl) 6H),4.85 (m, 2H), 6.46 (d, 1H), 6.81 (s, 1H), 7.02 amino]pyridin-3- (d, 1H),7.37 (m, 1H), 7.83 (d, 1H), 8.40 (m, 1H), yl}methyl)amino]- 8.80 (m,1H), 9.69-9.73 (m, 2H), 13.64 (s, 1H). 1H-pyrazolo[4,3- Using6-(2-cyclopropyl-5-fluoro-4-methoxyphenyl)- c]pyridine-3-carboxamideN-methyl-4-[({2-[methyl(methylsulfonyl)amino]pyridin-3-yl}methyl)amino]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazolo[4,3-c]pyridine-3-carboxamide (Preparation 110). 506-[5-fluoro-4-hydroxy- MS m/z 597 [M + H]⁺ 2-(2,2,2-trifluoroeth- ¹H NMR(400 MHz, DMSO-d₆): δ ppm 2.86 (d, 3H), yl)phenyl]-4-({5-methoxy- 2.98(s, 3H), 3.04 (s, 3H), 3.64 (m, 2H), 4.61 (m, 2-[methyl(methylsulfonyl)1H), 4.82 (m, 1H), 6.63 (dd, 1H), 6.70 (s, 1H), 6.76amino]benzyl}amino)- (m, 1H), 6.95 (d, 1H), 7.19-7.27 (m, 2H), 8.84 (m,1H), N-methyl-1H-pyrazolo[4,3- 9.50 (s, 1H), 9.70 (m, 1H), 10.09 (s,1H), 13.70 (s, 1H). c]pyridine-3-carboxamide Using6-[5-fluoro-2-(2,2,2-trifluoroethyl)-4-{[2-(tri-methylsilyl)ethoxy]methoxy}phenyl]-4-({5-methoxy-2-[methyl(methylsulfonyl)amino]benzyl}amino)-N-methyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazolo[4,3-c]pyridine-3-carboxamide (Preparation 46). 51 6-[5-fluoro-4-hydroxy- MSm/z 583 [M + H]⁺ 2-(2,2,2-trifluoroeth- ¹H NMR (400 MHz, DMSO-d₆): δ ppm2.86 (d, 3H), yl)phenyl]-N-methyl-4- 3.06 (s, 3H), 3.13 (s, 3H), 3.60(m, 2H), 4.95 (m, [({3-[methyl(methyl- 2H), 6.68 (s, 1H), 6.96 (d, 1H),7.16 (d, 1H), 8.49 (s, sulfonyl)amino]pyrazin- 1H), 8.59 (s, 1H), 8.80(m, 1H), 9.85 (m, 1H), 10.10 2-yl}methyl)amino]- (s, 1H), 13.68 (s, 1H).1H-pyrazolo[4,3- Using6-[5-fluoro-4-methoxy-2-(2,2,2-trifluoroethyl)phe-c]pyridine-3-carboxamidenyl]-N-methyl-4-[({3-[methyl(methylsulfonyl)amino]pyrazin-2-yl}methyl)amino]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazolo[4,3-c]pyridine-3-carboxamide (Preparation 47). 524-[({2-[ethyl(methyl- MS m/z 582 [M + H]⁺ sulfonyl)-amino]pyridin- ¹HNMR (400 MHz, DMSO-d₆): δ ppm 0.86 (t, 3H), 3-yl}methyl)amino]-6- 3.07(s, 3H), 3.55-3.67 (m, 4H), 4.84 (m, 2H), 6.72 [5-fluoro-4-hydroxy-2-(s, 1H), 6.95 (d, 1H), 7.19 (d, 1H), 7.38 (m, 1H),(2,2,2-trifluoroethyl)phenyl]- 7.82 (d, 1H), 7.87 (br s, 1H), 8.22 (brs, 1H), 8.44 1H-pyrazolo[4,3- (m, 1H), 9.80 (m, 1H), 10.07 (s, 1H),13.71 (s, 1H). c]pyridine-3-carboxamide UsingN-(2,4-dimethoxybenzyl)-4-[({2-[ethyl(methylsul-fonyl)-amino]pyridin-3-yl}methyl)amino]-6-[5-fluoro-4-methoxy-2-(2,2,2-trifluoroethyl)phenyl]-1-{[2-(trimethyl-silyl)ethoxy]methyl}-1H-pyrazolo[4,3-c]pyridine-3- carboxamide(Preparation 52). 53 6-[5-fluoro-4-hydroxy- MS m/z 582 [M + H]⁺2-(2,2,2-trifluoroeth- ¹H NMR (400 MHz, DMSO-d₆): δ ppm 2.86 (d, 3H),yl)phenyl]-N-methyl-4- 3.08 (s, 3H), 3.12 (s, 3H), 3.62 (q, 2H), 4.83(m, [({2-[methyl(methyl- 2H), 6.73 (s, 1H), 6.95 (d, 1H), 7.21 (d, 1H),7.36 sulfonyl)amino]pyridin- (m, 1H), 7.79 (d, 1H), 8.41 (m, 1H), 8.85(m, 1H), 3-yl}methyl)amino]- 9.80 (m, 1H), 10.10 (s, 1H), 13.73 (s, 1H).1H-pyrazolo[4,3- Using 6-[5-fluoro-4-methoxy-2-(2,2,2-trifluoroeth-c]pyridine-3-carboxamideyl)phenyl]-N-methyl-4-[({2-[methyl(methylsulfonyl)ami-no]pyridin-3-yl}methyl)amino]-1-{[2-(trimethylsilyl)eth-oxy]methyl}-1H-pyrazolo[4,3-c]pyridine-3-carboxamide (Preparation 53).54 6-[5-fluoro-4-hydroxy- MS m/z 660 [M + H]⁺ 2-(2,2,2-trifluoroeth- ¹HNMR (400 MHz, DMSO-d₆): δ ppm 2.86 (d, 3H), yl)phenyl]-4-({5-hydroxy-3.02 (s, 3H), 3.61 (m, 2H), 4.61 (m, 1H), 4.83 (m, 2-[methyl(pyridin-3-1H), 6.39 (d, 1H), 6.50 (m, 1H), 6.71 (s, 1H), 6.80ylsulfonyl)amino]ben- (m, 1H), 6.95 (d, 1H), 7.16-7.24 (m, 2H), 7.65 (m,zyl}amino)-N-methyl- 1H), 8.06 (m, 1H), 8.78 (s, 1H), 8.87 (m, 1H), 9.571H-pyrazolo[4,3- (s, 1H), 9.74 (m, 1H), 10.08 (s, 1H), 13.71 (br s, 1H).c]pyridine-3-carboxamide Using6-[5-fluoro-4-methoxy-2-(2,2,2-trifluoroeth-yl)phenyl]-4-({5-methoxy-2-[methyl(pyridin-3-ylsul-fonyl)amino]benzyl}amino)-N-methyl-1-{[2-(trimethyl-silyl)-ethoxy]methyl}-1H-pyrazolo[4,3-c]pyridine-3- carboxamide(Preparation 54).

Example 556-[5-Fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-N-methyl-4-[({3-[methyl(methylsulfonyl)amino]pyridin-2-yl}methyl)amino]-1H-pyrazolo[4,3-c]pyridine-3-carboxamide

A solution of6-[5-fluoro-2-(2,2,2-trifluoroethyl)-4-{[2-(trimethylsilyl)ethoxy]methoxy}phenyl]-N-methyl-4-[({3-[methyl(methylsulfonyl)amino]pyridin-2-yl}methyl)amino]-1-{[2-(trimethylsilyl)-ethoxy]methyl}-1H-pyrazolo[4,3-c]pyridine-3-carboxamide(Preparation 43, 110 mg, 0.13 mmol) in TFA (5 mL) was stirred at roomtemperature for 30 minutes. The reaction was concentrated in vacuo,dissolved in MeOH and cooled in ice-water. Ethylene diamine was addeddropwise and stirred for 1 hour. The reaction was quenched by theaddition of water and extracted into EtOAc. The organic layer wascollected, dried over sodium sulfate and concentrated in vacuo. Theresidue was purified using Preparative HPLC to afford the title compound(18 mg, 26%). ¹H NMR (400 MHz, DMSO-d₆): δ ppm 2.84 (d, 3H), 3.07 (s,6H), 3.61 (m, 2H), 4.70-5.20 (br m, 2H), 6.66 (s, 1H), 6.94 (d, 1H),7.16 (d, 1H), 7.37 (m, 1H), 7.92 (m, 1H), 8.47 (m, 1H), 9.77 (m, 1H),10.08 (br s, 1H), 13.63 (br s, 1H). MS m/z 582 [M+H]⁺

The following Examples (Examples 56-73) were prepared according to themethod described for Example 55 using the appropriate pyrazolo-pyridineand

Purification Method below if different from the method described

Purification Method H: Preparative TLC.

Purification Method I: Preparative HPLC.

Ex Name Data 56 6-(2-ethyl-5-fluoro-4- MS m/z 604 [M + H]⁺hydroxy-phenyl)-4-({2- ¹H NMR (400 MHz, DMSO-d₆): δ ppm 0.89 (t, 3H),[methyl(methylsulfo- 2.44 (s, 3H), 3.04 (s, 3H), 3.11 (s, 3H), 3.32 (m,nyl)amino]benzyl}amino)- 2H), 4.75 (m, 1H), 5.00 (m, 1H), 6.70 (s, 1H),6.78 N-(6-methylpyridin-3- (d, 1H), 7.06 (d, 1H), 7.24-7.32 (m, 3H),7.42-7.49 yl)-1H-pyrazolo[4,3- (m, 2H), 8.13 (dd, 1H), 8.87 (d, 1H),9.25 (t, 1H), c]pyridine-3- 9.79 (s, 1H), 10.83 (s, 1H), 13.89 (s, 1H).carboxamide Using 6-(2-ethyl-5-fluoro-4-{[2-(trimethylsilyl)ethoxy]methoxy}phenyl)-4-({2-[methyl(methylsulfonyl)amino]benzyl}amino)-N-(6-methylpyridin-3-yl)-1-{[2-(trimethylsilyl)eth-oxy]methyl}-1H-pyrazolo[4,3-c]pyridine-3- carboxamide (Preparation 20)and PM H. 57 6-(5-fluoro-4-hydroxy- MS m/z 610 [M + H]⁺ 2-(2,2,2- ¹H NMR(400 MHz, DMSO-d₆): δ ppm 2.83 (d, 3H), trifluoroethyl)phenyl)- 3.00 (s,3H), 3.64 (m, 2H), 4.84 (br m, 2H), 6.70 (s, N-methyl-4-((1,3,3- 1H),6.96 (d, 1H), 7.19-7.46 (m, 5H), 8.83 (m, 1H), trimethylureido)- 9.74(m, 1H), 10.09 (s, 1H), 13.70 (s, 1H). benzyl)amino)-1H- Using6-(5-fluoro-2-(2,2,2-trifluoro-ethyl)-4-((2- pyrazolo[4,3-(trimethylsilyl)ethoxy)-methoxy)phenyl)-N-methyl-1- c]pyridine-3-((2-(trimethylsilyl)ethoxy)methyl)-4-((2-(1,3,3- carboxamidetrimethylureido)benz-yl)amino)-1H-pyrazolo[4,3- c]pyridine-3-carboxamide(Preparation 13) and PM H. 58 6-(5-fluoro-4-hydroxy- MS m/z 633 [M + H]⁺2-(2,2,2- ¹H NMR (400 MHz, DMSO-d₆): δ ppm 2.85 (d, 3H),trifluoroethyl)phenyl)- 2.99 (s, 3H), 3.66 (m, 2H), 4.74 (m, 1H), 4.97(m, N-methyl-4-((2-(N- 1H), 6.71 (m, 2H), 6.96 (m, 1H), 7.17-7.28 (m,3H), methyl-1H-pyrazole-4- 7.40 (m, 1H), 7.73 (s, 1H), 8.30 (s, 1H),8.83 (m, sulfonamido)benzyl)ami- 1H), 9.76 (m, 1H), 10.10 (s, 1H), 13-71(s, 1H), no)-1H-pyrazolo[4,3- 13.75 (s, 1H). c]pyridine-3- Using6-(5-fluoro-2-(2,2,2-trifluoroethyl)-4-((2- carboxamidetrimethylsilyl)ethoxy)methoxy)phenyl)-N-methyl-4-((2-(N-methyl-1H-pyrazole-4-sulfonamido)benzyl)ami-no)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide (Preparation 3) and PM H. 594-((2-N,1-dimethyl-1H- MS m/z 647 [M + H]⁺ imidazole-4- ¹H NMR (400 MHz,DMSO-d₆): δ ppm 2.84 (d, 3H), sulfonamido)benzyl)ami- 3.08 (s, 3H), 3.70(m, 5H), 4.68 (m, 1H), 4.95 (m, do)-6-(5-fluoro-4- 1H), 6.71 (s, 1H),6.96 (m, 2H), 7.16-7.26 (m, 3H), hydroxy-2-(2,2,2- 7.36 (m, 1H), 7.72(s, 1H), 7.88 (s, 1H), 8.82 (m, trifluoroethyl)phenyl)- 1H), 9.73 (m,1H), 10.08 (s, 1H), 13.69 (s, 1H). N-methyl-1H- Using4-((2-(N,1-dimethyl-1H-imidazole-4- pyrazolo[4,3-sulfonamido)benzyl)amino)-6-(5-fluoro-2-(2,2,2- c]pyridine-3-trifluoroethyl)-4-((2-(trimethylsilyl)ethoxy)meth- carboxamideoxy)phenyl)-N-methyl-1-((2-(trimethylsilyl)eth-oxy)methyl)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide (Preparation 8) andPM H. 60 6-[5-fluoro-4-hydroxy- MS m/z 625 [M + H]⁺ 2-(2,2,2- ¹H NMR(400 MHz, DMSO-d₆): δ ppm 2.84 (d, 3H), trifluoroethyl)phenyl]- 3.09 (s,3H), 3.26 (s, 3H), 3.44-3.68 (m, 6H), 4.73- 4-[(2-{(2-methoxy- 4.86 (m,2H), 6.70 (s, 1H), 6.94 (d, 1H), 7.21 (d, ethyl)sulfonyl](meth- 1H),7.30 (m, 2H), 7.38 (m, 1H), 7.50 (m, 1H), 8.83 (m, yl)amino}benzyl)ami-1H), 9.77 (m, 1H), 10.08 (br s, 1H), 13.70 (br s, 1H). no]-N-methyl-1H-Using 6-[5-fluoro-2-(2,2,2-trifluoroethyl)-4-{[2- pyrazolo[4,3-(trimethylsilyl)ethoxy]methoxy}phenyl]-4-[(2-{[(2- c]pyridine-3-methoxyethyl)sulfonyl](methyl) carboxamideamino}benzyl)amino]-N-methyl-1-{[2-(trimethyl-silyl)ethoxy]methyl}-1H-pyrazolo-[4,3-c]pyridine- 3-carboxamide(Preparation 9) and PM H using 50% EtOAc in hexanes. 616-[5-fluoro-4-hydroxy- MS m/z 630 [M + H]⁺ 2-(2,2,2- ¹H NMR (400 MHz,DMSO-d₆): δ ppm 3.08 (s, 3H), trifluoroethyl)phenyl]-4- 3.69 (m, 2H),4.71 (m, 1H), 4.92 (m, 1H), 5.75 (d, ({2-[methyl(pyridin-3- 1H), 6.71(s, 1H), 6.97 (m, 1H), 7.17 (m, 1H), 7.24 ylsulfonyl)amino]ben- (d, 1H),7.30 (t, 1H), 7.44 (d, H), 7.65-7.86 (br s, zyl}amino)-1H- 1H), 8.07 (m,1H), 8.21 (br s, 1H), 8.79 (m, 1H), 8.89 pyrazolo[4,3- (m, 1H), 9.78 (t,1H), 10.09 (s, 1H), 13.69 (s, 1H). c]pyridine-3- Using6-[5-fluoro-2-(2,2,2-trifluoroethyl)-4-{[2- carboxamide(trimethylsilyl)ethoxy]methoxy}phenyl]-4-({2-[methyl(pyridin-3-ylsulfonyl)amino]benzyl}amino)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazolo[4,3-c]pyridine-3-carboxamide (Preparation 10). 62 6-[5-fluoro-4-hydroxy- MSm/z 568 [M + H]⁺ 2-(2,2,2- ¹H NMR (400 MHz, DMSO-d₆): δ ppm 3.09 (s,3H), trifluoroethyl)phenyl]- 3.12 (s, 3H), 3.65 (m, 2H), 4.81 (m, 2H),6.73 (s, 4-[({2-[methyl(methyl- 1H), 6.96 (d, 1H), 7.21 (d, 1H), 7.37(m, 1H), 7.82 sulfonyl)amino]pyridin- (m, 1H), 7.86 (br s, 1H), 8.21 (brs, 1H), 8.41 (m, 3-yl}methyl)amino]-1H- 1H), 9.81 (t, 1H), 10.09 (s,1H), 13.69 (s, 1H). pyrazolo[4,3- Using6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroeth- c]pyridine-3-yl)phenyl]-4-[({2-[methyl(methylsulfonyl)amino]pyridin- carboxamide3-yl}methyl)amino]-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide (Preparation 15). 634-[({2-[ethyl(methyl- MS m/z 596 [M + H]⁺ sulfonyl)amino]pyridin- ¹H NMR(400 MHz, DMSO-d₆): δ ppm 0.84 (t, 3H), 3-yl}methyl)amino]-6- 2.83 (d,3H), 3.05 (s, 3H), 3.52-3.64 (m, 4H), 4.83 [5-fluoro-4-hydroxy- (m, 2H),6.70 (s, 1H), 6.91 (d, 1H), 7.15 (d, 1H), 2-(2,2,2-trifluoroeth- 7.35(m, 1H), 7.76 (m, 1H), 8.42 (m, 1H), 8.83 (m, yl)phenyl]-N-methyl- 1H),9.76 (m, 1H), 10.04 (s, 1H), 13.71 (br s, 1H). 1H-pyrazolo[4,3- Using-[({2-[ethyl(methylsulfonyl)amino]pyridin-3- c]pyridine-3-yl}methyl)amino]-6-[5-fluoro-2-(2,2,2-trifluoroethyl)- carboxamide4-{[2-(trimethylsilyl)ethoxy]methoxy}phenyl]-N-methyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazolo[4,3-c]pyridine-3-carboxamide (Preparation 48) and PM I. 646-[5-fluoro-4-hydroxy- MS m/z 567 [M + H]⁺ 2-(2,2,2-trifluoroeth- ¹H NMR(400 MHz, DMSO-d₆): δ ppm 2.84 (d, 3H), yl)phenyl]-N-methyl- 3.76 (q,2H), 4.42 (s, 2H), 4.84 (m, 2H), 6.71 (s, 4-{[2-(sulfamoylmeth- 1H),6.87 (s, 2H), 6.98 (d, 1H), 7.20-7.36 (m, 5H), yl)benzyl]amino}-1H- 8.83(m, 1H), 9.75 (m, 1H), 10.10 (br s, 1H), 13.70 pyrazolo[4,3- (br s, 1H).c]pyridine-3- Using 6-[5-fluoro-2-(2,2,2-trifluoroethyl)-4-{[2-carboxamide (trimethylsilyl)ethoxy]methoxy}phenyl]-N-methyl-4-{[2-(sulfamoylmethyl)benzyl]amino}-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazolo[4,3- c]pyridine-3-carboxamide(Preparation 49). 65 6-[5-fluoro-4-hydroxy- MS m/z 715 [M + H]⁺2-(2,2,2-trifluoroeth- ¹H NMR (400 MHz, DMSO-d₆): δ ppm 3.00 (s, 3H),yl)phenyl]-4-{[2- 3.61-3.74 (m, 10H), 4.73 (m, 1H), 4.94 (m, 1H),(methyl{[6-(morpholin- 6.71 (s, 1H), 6.70 (d, 1H), 6.91 (d, 1H), 6.95(d, 1H), 4-yl)pyridin-3-yl]sul- 7.19-7.30 (m, 3H), 7.43 (m, 1H), 7.64(m, 1H), 7.86 fonyl}amino)benzyl]ami- (br s, 1H), 8.21 (br s, 1H), 8.28(m, 1H), 9.75 (m, no}-1H-pyrazolo[4,3- 1H), 10.10 (s, 1H), 13.68 (s,1H). c]pyridine-3- Using 6-[5-fluoro-2-(2,2,2-trifluoroethyl)-4-{[2-carboxamide (trimethylsilyl)-ethoxy]methoxy}phenyl]-4-{[2-(methyl{[6-(morpholin-4-yl)pyridin-3-yl]sulfonyl}amino)-benzyl]amino}-1-{[2-(trimethylsilyl)-ethoxy]methyl}-1H-pyrazolo[4,3-c]pyridine-3-carboxamide (Preparation 5). 66 6-[5-fluoro-4-hydroxy- MSm/z 680 [M + H]⁺ 2-(2,2,2-trifluoroeth- ¹H NMR (400 MHz, DMSO-d₆): δ ppm1.81 (m, 2H), yl)phenyl]-4-{[2- 2.29 (m, 6H), 3.12 (s, 3H), 3.23 (m,2H), 3.57 (m, (methyl{[3-(morpholin- 4H), 3.62 (m, 2H), 4.70-5.00 (m,2H), 6.70 (s, 1H), 4-yl)propyl]sulfonyl}- 6.95 (d, 1H), 7.22 (d, 1H),7.31-7.34 (m, 2H), 7.41- amino)benzyl]amino}- 7.46 (m, 2H), 7.84 (s,1H), 8.20 (s, 1H), 9.75 (m, 1H-pyrazolo[4,3- 1H), 10.08 (s, 1H), 13.67(s, 1H). c]pyridine-3- Using 6-[5-fluoro-2-(2,2,2-trifluoroethyl)-4-{[2-carboxamide (trimethylsilyl)ethoxy]methoxy}phenyl]-4-{[2-(methyl{[3-(morpholin-4-yl)propyl]sulfonyl}ami-no)benzyl]amino}-1-{[2-(trimethylsilyl)ethoxy]meth-yl}-1H-pyrazolo[4,3-c]pyridine-3-carboxamide (Preparation 2). 676-[5-fluoro-4-hydroxy- MS m/z 596 [M + H]⁺ 2-(2,2,2-trifluoroeth- ¹H NMR(400 MHz, DMSO-d₆): δ ppm 2.21 (s, 3H), yl)phenyl]-N-methyl-4- 2.86 (d,3H), 3.05 (s, 3H), 3.09 (s, 3H), 3.54 (m, [({5-methyl-2- 2H), 4.77 (m,2H), 6.72 (s, 1H), 6.95 (d, 1H), 7.19 [methyl(methylsulfon- (d, 1H),7.59 (s, 1H), 8.23 (s, 1H), 8.83 (m, 1H), yl)amino]pyridin-3- 9.78 (m,1H), 10.09 (br s, 1H), 13.72 (br s, 1H). yl}methyl)amino]-1H- Using6-[5-fluoro-2-(2,2,2-trifluoroethyl)-4-{[2- pyrazolo[4,3-(trimethylsilyl)ethoxy]methoxy}phenyl]-N-methyl-4- c]pyridine-3-[({5-methyl-2-[methyl(methylsulfonyl)amino]pyridin- carboxamide3-yl}methyl)amino]-1-{[2-(trimethylsilyl)ethoxy]meth-yl}-1H-pyrazolo[4,3-c]pyridine-3-carboxamide (Preparation 44). 686-[5-fluoro-4-hydroxy- MS m/z 644 [M + H]⁺ 2-(2,2,2-trifluoroeth- ¹H NMR(400 MHz, DMSO-d₆): δ ppm 2.84 (d, 3H), yl)phenyl]-N-methyl-4- 3.07 (s,3H), 3.62 (m, 2H), 4.74 (m, 1H), 4.93 (m, ({2-[methyl(pyridin-3- 1H),6.66 (d, 1H), 6.71 (s, 1H), 6.96 (d, 1H), 7.15- ylsulfonyl)amino]- 7.23(m, 2H), 7.28 (t, 1H), 7.42 (m, 1H), 7.65 (m, benzyl}amino)-1H- 1H),8.06 (m, 1H), 8.80-8.83 (m, 2H), 8.89 (m, 1H), pyrazolo[4,3- 9.76 (m,1H), 10.07 (s, 1H), 13.70 (s, 1H). c]pyridine-3- Using6-[5-fluoro-2-(2,2,2-trifluoro-ethyl)-4-{[2- carboxamide(trimethylsilyl)-ethoxy]methoxy}phenyl]-N-methyl-4-({2-[methyl(pyridin-3-ylsulfonyl)-amino]benzyl}amino)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazolo[4,3-c]pyridine-3-carboxamide (Preparation 45) and PM H using 4% MeOH in DCM.69 6-[5-fluoro-4-hydroxy- MS m/z 658 [M + H]⁺ 2-(2,2,2-trifluoroeth- ¹HNMR (400 MHz, DMSO-d₆): δ ppm 2.58 (s, 3H), yl)phenyl]-N-methyl-4- 2.85(d, 3H), 3.05 (s, 3H), 3.65 (m, 2H), 4.74 (m, [(2-{methyl[(6-methyl-1H), 4.93 (m, 1H), 6.68 (d, 1H), 6.71 (s, 1H), 6.96 pyridin-3-yl)sulfo-(d, 1H), 7.16-7.23 (m, 2H), 7.29 (t, 1H), 7.43 (d, nyl]amino}benzyl)ami-1H), 7.50 (d, 1H), 7.93 (m, 1H), 8.65 (m, 1H), 8.82 no]1H-pyrazolo[4,3-(m, 1H), 9.75 (m, 1H), 10.08 (s, 1H), 13.70 (s, 1H). c]pyridine-3- Using6-[5-fluoro-2-(2,2,2-trifluoroethyl)-4-{[2- carboxamide(trimethylsilyl)ethoxy]methoxy}phenyl]-N-methyl-4-[(2-{methyl[(6-methylpyridin-3-yl)sulfonyl]amino}-benzyl)amino]-1-{[2-(trimethylsilyl)-ethoxy]methyl}-1H-pyrazolo[4,3-c]pyridine-3-carboxamide (Preparation 6). 706-[5-fluoro-4-hydroxy- MS m/z 644 [M + H]⁺ 2-(2,2,2-trifluoroeth- ¹H NMR(400 MHz, DMSO-d₆): δ ppm 2.58 (s, 3H), yl)phenyl]-4-[(2-{meth- 3.06 (s,3H), 3.67 (m, 2H), 4.71 (m, 1H), 4.92 (m, yl[(6-methylpyridin-3- 1H),6.69 (d, 1H), 6.71 (s, 1H), 6.97 (d, 1H), 7.16- yl)sulfonyl]amino}ben-7.24 (m, 2H), 7.30 (t, 1H), 7.46 (d, 1H), 7.50 (d, 1H), zyl)amino]-1H-7.91 (br s, 1H), 7.93 (dd, 1H), 8.21 (br s, 1H), 8.65 pyrazolo[4,3- (m,1H), 9.77 (m, 1H), 10.09 (s, 1H), 13.68 (s, 1H). c]pyridine-3- Using6-[5-fluoro-2-(2,2,2-trifluoroethyl)-4-{[2- carboxamide(trimethylsilyl)ethoxy]methoxy}phenyl]-4-[(2-{meth-yl[(6-methylpyridin-3-yl)sulfonyl]amino}benzyl)amino]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazolo[4,3-c]pyridine-3-carboxamide (Preparation 7) and using aqueous ammoniainstead of ethylene diamine. 71 4-[({5-chloro-2- MS m/z 616 [M + H]⁺[ethyl(methylsulfo- ¹H NMR (400 MHz, DMSO-d₆): δ ppm 0.85 (t, 3H),nyl)amino]pyridin-3- 3.49-3.65 (m, 4H), 4.81 (m, 2H), 6.74 (s, 1H), 6.95yl}methyl)amino]-6-[5- (d, 1H), 7.18 (d, 1H), 7.81 (m, 1H), 7.90 (br s,1H), fluoro-4-hydroxy-2- 8.24 (br s, 1H), 8.51 (m, 1H), 9.80 (m, 1H),10.08 (s, (2,2,2-trifluoroeth- 1H), 13.74 (s, 1H). yl)phenyl]-1H- UsingN-tert-butyl-4-[({5-chloro-2-[ethyl(methylsulfo- pyrazolo[4,3-nyl)amino]pyridin-3-yl}methyl)amino]-6-[5-fluoro-2- c]pyridine-3-(2,2,2-trifluoroethyl)-4-{[2-(trimethylsilyl)eth- carboxamideoxy]methoxy} phenyl]-1-{[2-(trimethylsilyl)-eth-oxy]methyl}-1H-pyrazolo[4,3-c]pyridine-3-carboxamide (Preparation 50).72 4-[({5-chloro-2- MS m/z 602 [M + H]⁺ [methyl(methylsulfo- ¹H NMR (400MHz, DMSO-d₆): δ ppm 3.07 (s, 3H), nyl)amino]pyridin-3- 3.16 (s, 3H),3.58 (q, 2H), 4.79 (m, 2H), 6.75 (s, yl}methyl)amino]-6-[5- 1H), 6.96(d, 1H), 7.18 (d, 1H), 7.80 (d, 1H), 7.89 fluoro-4-hydroxy-2- (br s,1H), 8.23 (br s, 1H), 8.47 (d, 1H), 9.82 (m, (2,2,2-trifluoroeth- 1H),10.10 (s, 1H), 13.73 (s, 1H). yl)phenyl]-1H- UsingN-tert-butyl-4-[({5-chloro-2-[methyl(methylsulfo- pyrazolo[4,3-nyl)amino]pyridin-3-yl}methyl)amino]-6-[5-fluoro-2- c]pyridine-3-(2,2,2-trifluoroethyl)-4-{[2-(trimethylsilyl)eth- carboxamideoxy]methoxy} phenyl]-1-{[2-(trimethylsilyl)-eth-oxy]methyl}-1H-pyrazolo[4,3-c]pyridine-3-carboxamide (Preparation 51).73 6-(2-ethyl-5-fluoro-4- MS m/z 528 [M + H]⁺ hydroxyphenyl)-N- ¹H NMR(400 MHz, DMSO-d₆): δ ppm 0.87 (t, 3H), methyl-4-({2- 2.53 (m, 2H), 2.84(s, 3H), 3.01 (s, 3H), 3.39 (m, [methyl(sulfamoyl)- 2H), 4.70 (br s,1H), 5.00 (br s, 1H), 6.54 (s, 1H), amino]benzyl}amino)- 6.79 (d, 1H),7.03 (m, 2H), 7.24 (m, 1H), 7.37 (m, 1H-pyrazolo[4,3- 1H), 7.43 (m, 1H),8.78 (m, 1H), 9.60 (m, 1H), 9.75 c]pyridine-3- (s, 1H), 13.60 (s, 1H).carboxamide Using 6-(2-ethyl-5-fluoro-4-{[2-(trimethylsilyl)eth-oxy]methoxy}phenyl)-N-methyl-4-({2-[methyl(sulfamoyl)-amino]benzyl}amino)-1-{[2-(trimethylsilyl)ethoxy]meth-yl}-1H-pyrazolo[4,3-c]pyridine-3-carboxamide (Preparation 1).

Example 746-(5-Fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl)-4-((N-(2-hydroxyethyl)-(sulfamoyl)(methyl)aminobenzyl)amino)-N-methyl-1H-pyrazolo[4,3-c]pyridine-3-carboxamide

The title compound was prepared according to the method described forExample 55 using6-(5-fluoro-2-(2,2,2-trifluoroethyl)-4-((2-(trimethylsilyl)ethoxy)-methoxy)phenyl)-N-methyl-4-((2-(N-methyl-2-oxoxazolidine-3-sulfonamido)benzyl)-amino)-1-((2-(trimethylsilyl)-ethoxy)-methyl)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide(Preparation 58). The residue was treated with 6M NaOH (0.5 mL) at 0° C.and stirred at room temperature for 18 hours. The reaction was acidifiedwith HCl at 0° C., and the resulting precipitate was filtered, extractedinto EtOAc and concentrated in vacuo. The residue was purified usingpreparative TLC. ¹H NMR (400 MHz, DMSO-d₆): δ ppm 1.07 (m, 3H), 2.84 (s,3H), 3.02 (s, 3H), 3.39 (m, 2H), 3.69 (m, 2H), 4.70 (m, 2H), 4.90 (br m,2H), 6.94 (s, 1H), 6.96 (m, 1H), 7.20-7.46 (m, 5H), 8.82 (m, 1H), 9.71(m, 1H), 10.10 (br s, 1H), 13.70 (s, 1H). MS m/z 626 [M+H]⁺

Example 756-[5-Fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-N-{6-[(2-hydroxyethyl)amino]pyridin-3-yl}-4-({5-hydroxy-2-[methyl(methylsulfonyl)amino]benzyl}amino)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide

To a solution of6-[5-fluoro-2-(2,2,2-trifluoroethyl)-4-{[2-(trimethylsilyl)ethoxy]-methoxy}phenyl]-4-({5-methoxy-2-[methyl(methylsulfonyl)amino]benzyl}amino)-1-{[2-(trimethyl-silyl)ethoxy]methyl}-1H-pyrazolo[4,3-c]pyridine-3-carboxylicacid (Preparation 11, 100 mg, 0.12 mmol) in DCM (3 mL) was added borontribromide (0.08 mL, 0.82 mmol) and the reaction was stirred at roomtemperature for 30 minutes. The reaction was concentrated in vacuo andtriturated with ether/pentane. The resulting solid was dissolved in DMF(2 mL) and 2-[(5-aminopyridin-2-yl)amino]ethanol (51 mg, 0.33 mmol)followed by DIPEA (0.07 mL, 0.17 mmol) were added. HATU (159 mg, 0.42mmol) was added and the reaction stirred at room temperature for 18hours. The reaction was partitioned between EtOAc and water, the organiclayer was collected, dried over sodium sulfate and concentrated invacuo. The residue was purified using preparative TLC to afford thetitle compound (15 mg, 13%). ¹H NMR (400 MHz, DMSO-d₆): δ ppm 2.98 (s,3H), 3.03 (s, 3H), 3.32 (m, 2H), 3.52 (m, 2H), 3.64 (m, 2H), 4.60 (m,1H), 4.71 (m, 1H), 4.83 (m, 1H), 6.45 (m, 1H), 6.53 (d, 1H), 6.63 (dd,1H), 6.75 (s, 1H), 6.78 (m, 1H), 6.96 (d, 1H), 7.21-7.26 (m, 2H), 7.78(dd, 1H), 8.31 (s, 1H), 9.46 (m, 2H), 10.10 (s, 1H), 10.48 (s, 1H),13.86 (s, 1H). MS m/z 719 [M+H]⁺

Example 766-[5-Fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-4-({2-[methyl(methylsulfonyl)amino]-benzyl}amino)-N-(6-methylpyridin-3-yl)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide

To a solution of6-[5-fluoro-2-(2,2,2-trifluoroethyl)-4-{[2-(trimethylsilyl)ethoxy]methoxy}-phenyl]-4-({2-[methyl(methylsulfonyl)amino]benzyl}amino)-1-{[2-(trimethyl-silyl)ethoxy]-methyl}-1H-pyrazolo[4,3-c]pyridine-3-carboxylicacid (Preparation 12, 100 mg, 0.12 mmol) in DMF (3 mL) was added6-methylpyridin-3-amine (65 mg, 0.60 mmol), DIPEA (0.13 mL, 0.73 mmol)and BOP (267 mg, 0.60 mmol) and the reaction was stirred at roomtemperature for 18 hours before concentrating in vacuo. The residue waspartitioned between ice-water and EtOAc, the organic layer wascollected, washed with brine, dried over sodium sulfate and concentratedin vacuo. The residue was purified using silica gel columnchromatography eluting with 5% MeOH in DCM. The residue was treated withTFA (3 mL) and stirred at room temperature for 30 minutes. The reactionwas concentrated in vacuo, dissolved in MeOH and cooled in ice-water.Ethylene diamine was added until the solution became basic, withstirring for 15 minutes. The solution was concentrated in vacuo andpurified using preparative HPLC to afford the title compound (35 mg,29%). ¹H NMR (400 MHz, DMSO-d₆): δ ppm 2.45 (s, 3H), 3.04 (s, 3H), 3.11(s, 3H), 3.62 (m, 2H), 4.80 (m, 1H), 4.95 (m, 1H), 6.77 (s, 1H), 6.96(d, 1H), 7.20-7.33 (m, 4H), 7.41 (m, 1H), 7.49 (m, 1H), 8.13 (dd, 1H),8.87 (d, 1H), 9.33 (t, 1H), 10.85 (br s, 1H). MS m/z 658 [M+H]⁺

Example 776-[5-Fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-4-({2-[methyl(methylsulfonyl)amino]benzyl}amino)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide

6-(4-(Benzyloxy)-5-fluoro-2-(2,2,2-trifluoroethyl)phenyl)-N-(tert-butyl)-4-((2-(N-methylmethylsulfonamido)benzyl)amino)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide(Preparation 27, 60 mg, 0.07 mmol) was treated with TFA (8 mL) andheated to reflux for 18 hours. The reaction was cooled, concentrated invacuo, quenched by the addition of saturated aqueous sodium bicarbonatesolution and extracted into EtOAc. The organic layer was collected,dried over sodium sulfate and concentrated in vacuo. The crude residuewas purified using preparative TLC to afford the title compound (21 mg,51%). ¹H NMR (400 MHz, DMSO-d₆): δ ppm 3.04 (s, 3H), 3.14 (s, 3H), 3.69(m, 2H), 4.70 (br m, 1H), 4.90 (m, 1H), 6.70 (s, 1H), 6.96 (d, 1H), 7.22(d, 1H), 7.27-7.34 (m, 2H), 7.40 (m, 1H), 7.49 (m, 1H), 7.85 (br s, 1H),8.20 (br s, 1H), 9.75 (m, 1H), 10.09 (s, 1H), 13.70 (s, 1H). MS m/z 567[M+H]⁺

Example 786-[5-Fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-4-[({5-fluoro-2-[methyl(methyl-sulfonyl)amino]pyridin-3-yl}methyl)amino]-1H-pyrazolo[4,3-c]pyridine-3-carboxamide

6-(4-Benzyloxy)-5-fluoro-2-(2,2,2-trifluoroethyl)phenyl)-N-(tert-butyl)-4-(((5-fluoro-2-(N-meth-ylmethylsulfonamido)pyridin-3-yl)methyl)amino)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo-[4,3-c]pyridine-3-carboxamide(Preparation 55, 80 mg, 0.10 mmol) was treated with TFA (10 mL) andheated to reflux for 18 hours. The reaction was cooled, concentrated invacuo and partitioned between saturated aqueous sodium bicarbonatesolution and EtOAc. The organic layer was collected, dried over sodiumsulfate and concentrated in vacuo. The residue was purified usingpreparative TLC to afford the title compound (20 mg, 35%). ¹H NMR (400MHz, DMSO-d₆): δ ppm 3.07 (s, 3H), 3.12 (s, 3H), 3.57 (q, 2H), 4.80 (m,2H), 6.75 (s, 1H), 6.95 (d, 1H), 7.18 (d, 1H), 7.62 (dd, 1H), 7.89 (brs, 1H), 8.24 (br s, 1H), 8.42 (m, 1H), 9.85 (m, 1H), 10.11 (br s, 1H),13.73 (br s, 1H). MS m/z 586 [M+H]⁺

The following Examples (Examples 79-91) were prepared according to themethod described for Example 78 using the appropriate pyrazolo-pyridine.

Example Name Data 79 4-[({2-[ethyl(methyl- MS m/z 600 [M + H]⁺sulfonyl)amino]-5- ¹H NMR (400 MHz, DMSO-d₆): δ ppm 0.85 (t, 3H),fluoropyridin-3- 3.07 (s, 3H), 3.51 (q, 2H), 3.61 (q, 2H), 4.08 (m,yl}methyl)amino]-6-[5- 1H), 6.74 (s, 1H), 6.94 (d, 1H), 7.19 (d, 1H),7.61 fluoro-4-hydroxy-2- (m, 1H), 7.90 (br s, 1H), 8.24 (br s, 1H), 8.45(s, (2,2,2-trifluoroeth- 1H), 9.84 (t, 1H), 10.08 (s, 1H), 13.74 (s,1H). yl)phenyl]-1H- Using6-(4-benzyloxy)-5-fluoro-2-(2,2,2-trifluoroeth- pyrazolo[4,3-yl)phenyl)-N-(tert-butyl)-4-(((5-fluoro-2-(N-ethyl- c]pyridine-3-methylsulfonamido)pyridin-3-yl)methyl)amino)-1-(tetra- carboxamidehydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine-3- carboxamide(Preparation 56). 80 4-[({3-[ethyl(methylsul- MS m/z 583 [M + H]⁺fonyl)-amino]pyrazin- ¹H NMR (400 MHz, DMSO-d₆): δ ppm 0.86 (t, 3H),2-yl}methyl)amino]-6- 3.10 (s, 3H), 3.59 (q, 2H), 3.68 (q, 2H), 4.97 (m,[5-fluoro-4-hydroxy-2- 2H), 6.60 (s, 1H), 6.97 (d, 1H), 7.15 (d, 1H),7.82 (br (2,2,2-trifluoroeth- s, 1H), 8.16 (br s, 1H), 8.56 (s, 1H),8.61 (s, 1H), yl)phenyl]-1H- 9.85 (br s, 1H), 10.09 (s, 1H), 13.66 (s,1H). pyrazolo[4,3- Using 6-(4-benzyloxy)-5-fluoro-2-(2,2,2-trifluoroeth-c]pyridine-3- yl)phenyl)-N-(tert-butyl)-4-(((3-(N-ethylmethylsul-carboxamide fonamido)pyrazin-2-yl)methyl)amino)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide (Preparation 57).81 6-[5-fluoro-4-hydroxy- MS m/z 581 [M + H]⁺ 2-(2,2,2-trifluoroeth- ¹HNMR (400 MHz, DMSO-d₆): δ ppm 2.20 (s, 3H), yl)phenyl]-4-({5-methyl-3.01 (s, 3H), 3.07 (s, 3H), 3.64 (m, 2H), 4.64 (m,2-[methyl(methylsulfo- 1H), 4.88 (m, 1H), 6.94 (s, 1H), 6.96 (d, 1H),7.14 nyl)amino]benzyl}amino)- (m, 1H), 7.21 (m, 2H), 7.37 (m, 1H), 7.84(br s, 1H), 1H-pyrazolo[4,3- 8.18 (br s, 1H), 9.69 9s, 1H), 10.09 (s,1H), 13.67 c]pyridine-3- (s, 1H). carboxamide Using6-(4-benzyloxy)-5-fluoro-2-(2,2,2-trifluoro-ethyl)phenyl)-N-(tert-butyl)-4-((5-methyl-2-(N-methyl-methylsulfonamido)benzyl)amino)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide (Preparation 28).82 4-((2-(N-ethylethyl- MS m/z 595 [M + H]⁺ sulfonamido)benzyl)ami- ¹HNMR (400 MHz, DMSO-d₆): δ ppm 0.90 (t, 3H), no)-6-(5-fluoro-4- 1.19 (t,3H), 3.19 (m, 2H), 3.51-3.64 (m, 4H), 4.70 hydroxy-2-(2,2,2- (m, 1H),4.87 (m, 1H), 6.69 (s, 1H), 6.94 (d, 1H), trifluoroethyl)phenyl)- 7.19(d, 1H), 7.30 (m, 2H), 7.42 (m, 2H), 7.85 (br s, 1H-pyrazolo[4,3- 1H),8.10 (br s, 1H), 9.77 (m, 1H), 10.06 (s, 1H), c]pyridine-3- 13.67 (s,1H). carboxamide Using 6-(4-benzyloxy)-5-fluoro-2-(2,2,2-trifluoroeth-yl)phenyl)-N-(tert-butyl)-4-((2-(N-ethylethylsulfon-amido)benzyl)amino)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide (Preparation 32). 834-((2-(N-ethylmethyl- MS m/z 599 [M + H]⁺ sulfonamido)-5- ¹H NMR (400MHz, DMSO-d₆): δ ppm 0.89 (t, 3H), fluorobenzyl)amino)- 3.02 (s, 3H),3.43-3.64 (m, 4H), 4.71 (m, 1H), 4.85 6-(5-fluoro-4-hydroxy- (m, 1H),6.72 (s, 1H), 6.93 (d, 1H), 7.10-7.19 (m, 2-(2,2,2-trifluoroeth- 3H),7.51 (m, 1H), 7.88 (br s, 1H), 8.22 (br s, 1H), yl)phenyl)-1H- 9.79 (m,1H), 10.05 (s, 1H), 13.71 (s, 1H). pyrazolo[4,3- Using6-(4-(benzyloxy)-5-fluoro-2-(2,2,2-trifluoro- c]pyridine-3-ethyl)phenyl)-N-(tert-butyl)-4-((2-(N-ethylmethyl- carboxamidesulfonamido)-5-fluorobenzyl)amino)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide (Preparation 34).84 4-((5-chloro-2-(N- MS m/z 615 [M + H]⁺ ethylmethylsulfon- ¹H NMR (400MHz, DMSO-d₆): δ ppm 1.01 (t, 3H), amido)benzyl)amino)- 3.16 (s, 3H),3.58-3.76 (m, 4H), 4.82 (m, 1H), 4.98 6-(5-fluoro-4-hydroxy- (m, 1H),6.85 (s, 1H), 7.06 (d, 1H), 7.32 (m, 1H), 2-(2,2,2-trifluoroeth- 7.52(m, 2H), 7.62 (m, 1H), 8.01 (br s, 1), 8.35 (br s, yl)phenyl)-1H- 1H),9.91 (t, 1H), 10.18 (s, 1H), 13.85 (s, 1H). pyrazolo[4,3- Using6-(4-(benzyloxy)-5-fluoro-2-(2,2,2-trifluoro- c]pyridine-3-ethyl)phenyl)-N-(tert-butyl)-4-((2-(N-ethylmethyl- carboxamidesulfonamido)-5-chlorobenzyl)amino)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide (Preparation 35).85 6-(5-fluoro-4-hydroxy- MS m/z 581 [M + H]⁺ 2-(2,2,2-trifluoroeth- ¹HNMR (400 MHz, DMSO-d₆): δ ppm 1.19 (t, 3H), yl)phenyl)-4-((2-(N- 3.11(s, 3H), 3.23-3.31 (m, 2H), 3.58 (q, 2H), 4.60- methylethylsulfon- 4.90(m, 2H), 6.70 (s, 1H), 6.95 (d, 1H), 7.21 (d, amido)benzyl)amino)- 1H),7.26-7.34 (m, 2H), 7.40-7.47 (m, 2H), 7.86 (br 1H-pyrazolo[4,3- s, 1H),8.21 (br s, 1H), 9.78 (t, 1H), 10.09 (s, 1H), c]pyridine-3- 13.68 (s,1H). carboxamide Using 6-(4-(benzyloxy)-5-fluoro-2-(2,2,2-trifluoroeth-yl)phenyl)-N-(tert-butyl)-4-((2-(N-methylethylsulfon-amido)benzyl)amino)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide (Preparation 37). 866-(5-fluoro-4-hydroxy- MS m/z 582 [M + H]⁺ 2-(2,2,2-trifluoroeth- ¹H NMR(400 MHz, DMSO-d₆): δ ppm 2.22 (s, 3H), yl)phenyl)-4-(((5-methyl- 3.05(s, 3H), 3.09 (s, 3H), 3.61 (q, 2H), 4.75 (m, 2-(N-methylmethylsulfon-2H), 6.72 (s, 1H), 6.96 (d, 1H), 7.19 (d, 1H), 7.61 (bramido)pyridin-3-yl)meth- s, 1H), 7.86 (br s, 1H), 8.23 (m, 2H), 9.77 (m,1H), yl)amino)-1H- 10.09 (s, 1H), 13.70 (s, 1H). pyrazolo[4,3- Using6-(4-(benzyloxy)-5-fluoro-2-(2,2,2-trifluoroeth- c]pyridine-3-yl)phenyl)-N-(tert-butyl)-4-(((5-methyl-2-(N-methyl- carboxamidemethylsulfonamido)pyridin-3-yl)methyl)amino)-1-(tetra-hydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine-3- carboxamide(Preparation 38). 87 4-[({2-[ethyl(methyl- MS m/z 596 [M + H]⁺sulfonyl)amino]-5- ¹H NMR (400 MHz, DMSO-d₆): δ ppm 0.86 (t, 3H),methylpyridin-3- 2.22 (s, 3H), 3.04 (s, 3H), 3.55-3.63 (m, 4H), 4.78yl}methyl)amino]-6-[5- (m, 2H), 6.72 (s, 1H), 6.94 (d, 1H), 7.20 (d,1H), fluoro-4-hydroxy-2- 7.60 (br s, 1H), 7.87 (br s, 1H), 8.22 (s, 1H),8.26 (s, (2,2,2-trifluoroeth- 1H), 9.76 (t, 1H), 10.07 (br s, 1H), 13.71(br s, 1H). yl)phenyl]-1H- Using6-(4-(benzyloxy)-5-fluoro-2-(2,2,2-trifluoroeth- pyrazolo[4,3-yl)phenyl)-N-(tert-butyl)-4-(((2-(N-ethylmethylsulfon- c]pyridine-3-amido)-5-methylpyridin-3-yl)methyl)amino)-1-(tetra- carboxamidehydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine-3- carboxamide(Preparation 33). 88 6-[5-fluoro-4-hydroxy- MS m/z 611 [M + H]⁺2-(2,2,2-trifluoroeth- ¹H NMR (400 MHz, DMSO-d₆): δ ppm 3.05 (s, 3H),yl)phenyl]-4-({5-fluoro- 3.08 (s, 3H), 3.58 (m, 2H), 4.70 (m, 1H), 4.83(m, 2-[methyl(methylsulfo- 1H), 6.73 (s, 1H), 6.94 (d, 1H), 7.09-7.22(m, 3H), nyl)amino]benzyl}amino)- 7.56 (m, 1H), 7.89 (s, 1H), 8.24 (s,1H), 9.80 (m, 1H-pyrazolo[4,3- 1H), 10.11 (br s, 1H), 13.72 (br s, 1H).c]pyridine-3- Using 6-(4-(benzyloxy)-5-fluoro-2-(2,2,2-trifluoro-carboxamide ethyl)phenyl)-N-(tert-butyl)-4-((5-fluoro-2-(N-methyl-methylsulfonamido)benzyl)amino)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide (Preparation 59).89 4-({5-chloro-2- MS m/z 601 [M + H]⁺ [methyl(methylsulfo- ¹H NMR (400MHz, DMSO-d₆): δ ppm 3.05 (s, 3H), nyl)amino]benzyl}amino)- 3.08 (s,3H), 3.56 (m, 2H), 4.66-4.82 (m, 2H), 6.73 6-[5-fluoro-4-hydroxy- (s,1H), 6.94 (d, 1H), 7.20 (d, 1H), 7.38 (m, 2H), 2-(2,2,2-trifluoroeth-7.53 (m, 1H), 7.88 (s, 1H), 8.22 (s, 1H), 9.77 (m, yl)phenyl]-1H- 1H),10.09 (s, 1H), 13.71 (br s, 1H). pyrazolo[4,3- Using6-(4-(benzyloxy)-5-fluoro-2-(2,2,2-trifluoro- c]pyridine-3-ethyl)phenyl)-N-(tert-butyl)-4-((5-chloro-2-(N-methyl- carboxamidemethylsulfonamido)benzyl)amino)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide (Preparation 30).90 4-({2-[ethyl(methyl- MS m/z 581 [M + H]⁺ sulfonyl)amino]benzyl} ¹HNMR (400 MHz, DMSO-d₆): δ ppm 0.88 (t, 3H), amino)-6-[5-fluoro-4- 3.02(s, 3H), 3.46-3.68 (m, 4H), 4.69 (m, 1H), 2.92 hydroxy-2-(2,2,2- (m,1H), 6.69 (s, 1H), 6.94 (d, 1H), 7.17 (d, 1H), trifluoroethyl)phenyl]-7.32 (m, 2H), 7.45 (m, 2H), 7.86 (br s, 1H), 8.22 (br 1H-pyrazolo[4,3-s, 1H), 9.76 (m, 1H), 10.08 (s, 1H), 13.69 (s, 1H). c]pyridine-3- Using6-(4-(benzyloxy)-5-fluoro-2-(2,2,2-trifluoro- carboxamideethyl)phenyl)-N-(tert-butyl)-4-((2-(N-ethylmethyl-sulfonamido)benzyl)amino)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide (Preparation 36). 914-({2-[ethyl(methyl- MS m/z 595 [M + H]⁺ sulfonyl)amino]-5- ¹H NMR (400MHz, DMSO-d₆): δ ppm 0.90 (t, 3H), methylbenzyl}amino)- 2.21 (s, 3H),2.99 (s, 3H), 3.46 (m, 1H), 3.61 (m, 6-[5-fluoro-4-hydroxy- 1H), 4.64(m, 1H), 4.86 (m, 1H), 6.69 (s, 1H), 6.92 2-(2,2,2-trifluoroeth- (d,1H), 7.12 (m, 1H), 7.18-7.21 (m, 2H), 7.30 (d, yl)phenyl]-1H- 1H), 7.84(s, 1H), 8.19 (s, 1H), 9.69 (m, 1H), 10.06 pyrazolo[4,3- (s, 1H), 13.67(s, 1H). c]pyridine-3- Using6-(4-(benzyloxy)-5-fluoro-2-(2,2,2-trifluoro- carboxamideethyl)phenyl)-N-(tert-butyl)-4-((2-(N-ethylmethyl-sulfonamido)-5-methylbenzyl)amino)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide (Preparation 31).

Example 926-[5-Fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-4-({5-hydroxy-2-[methyl(methylsulfonyl)amino]benzyl}amino)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide

6-(4-(Benzyloxy)-5-fluoro-2-(2,2,2-trifluoroethyl)phenyl)-N-(tert-butyl)-4-((5-methoxy-2-(N-methylmethylsulfonamido)benzyl)amino)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide(Preparation 29, 100 mg, 0.12 mmol) was heated to 100° C. in neat TFA(15 mL) for 18 hours. The reaction was cooled, concentrated in vacuo andpartitioned between saturated aqueous sodium bicarbonate solution andEtOAc. The organic layer was collected, dried over sodium sulfate andconcentrated in vacuo. The residue was purified using silica gel columnchromatography eluting with 55% EtOAc in hexanes. The residue wasstirred with neat boron tribromide (8 eq) at 0° C. for 4 hours. Thereaction was partitioned between DCM and saturated aqueous sodiumbicarbonate solution, the organic layer collected, washed with brine,dried over sodium sulfate and concentrated in vacuo. The residue waspurified using preparative TLC eluting with 5% MeOH in DCM to afford thetitle compound (30 mg, 51%). ¹H NMR (400 MHz, DMSO-d₆): δ ppm 2.98 (s,3H), 3.04 (s, 3H), 3.66 (m, 2H), 4.58 (m, 1H), 4.79 (m, 1H), 6.63 (dd,1H), 6.70 (s, 1H), 6.78 (m, 1H), 6.93 (d, 1H), 7.19-7.26 (m, 2H), 7.85(br s, 1H), 8.20 (br s, 1H), 9.50 (s, 1H), 9.70 (m, 1H), 10.08 (s, 1H),13.67 (s, 1H). MS m/z 583 [M+H]⁺

Example 936-(2-Ethyl-5-fluoro-4-hydroxyphenyl)-N-methyl-4-((2-(N-methylmethylsulfonamido)benzyl)amino)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide

To a solution ofN-(2-(((6-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)methyl)phenyl)-N-methylmethanesulfonamide(Preparation 272, 249 mg, 0.36 mmol) and methylamine in THF (3 mL, 2M)was added molybdenum hexacarbonyl (96 mg, 0.36 mmol) and palladiumacetate (5.7 mg, 0.025 mmol) followed by DBU (165 mg, 1.09 mmol) and thereaction was heated to 100° C. under microwave irradiation for 10minutes. The reaction was concentrated in vacuo, diluted with EtOAc andfiltered through celite. The filtrate was concentrated in vacuo andpurified using silica gel column chromatography followed by PreparativeTLC. The residue was dissolved in ethanol (7 mL) and hydrogenated withPd(OH)₂ (15 mg) at 40 psi for 16 hours. The reaction was filteredthrough celite and concentrated in vacuo. The residue was trituratedwith pentane and ether to afford the title compound as an off whitesolid (42 mg, 65%). ¹H NMR (400 MHz, DMSO-d₆): δ ppm 0.98 (t, 3H), 2.83(m, 4H), 3.07 (s, 3H), 3.18 (s, 3H), 3.39 (m, 1H), 4.90 (br m, 1H), 5.05(br m, 1H), 6.82 (m, 1H), 7.35-7.56 (m, 5H), 8.86 (m, 1H), 9.81 (t, 1H),10.02 (br s, 1H), 13.97 (br s, 1H). MS m/z 528 [M+H]⁺

Example 946-(5-Fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl-N-methyl-4-((2-(N-methylmethylsulfonamido)benzyl)amino)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide

The title compound was prepared according to the method described forPreparation 93 usingN-(2-(((6-(4-(benzyloxy)-5-fluoro-2-(2,2,2-trifluoroethyl)phenyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)methyl)phenyl)-N-methylmethanesulfonamide(Preparation 276). The residue was purified using silica gel columnchromatography eluting with 60% EtOAc in hexanes. ¹H NMR (400 MHz,DMSO-d₆): δ ppm 2.82 (d, 3H), 3.07 (s, 3H), 3.17 (s, 3H), 4.27 (m, 2H),4.91-5.01 (br m, 2H), 6.97 (m, 1H), 7.32-7.41 (m, 3H), 7.54 (m, 1H),7.67 (m, 1H), 8.87 (t, 1H), 9.91 (t, 1H), 10.37 (br s, 1H), 14.03 (br s,1H). MS m/z 582 [M+H]⁺

Example 956-(2-Ethyl-5-fluoro-4-hydroxyphenyl)-4-((2-(N-methylphenylsulfonamido)benzyl)amino)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide

To a solution of6-(2-ethyl-5-fluoro-4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-4-((2-(N-methylphenylsulfonamido)benzyl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo-[3,4-d]pyrimidine-3-carboxylicacid (Preparation 258, 300 mg, 837.14 mmol) in anhydrous THF (10 mL) wasadded NMM (0.06 mL, 0.57 mmol) and isobutylchloroformate (0.07 mL, 0.57mmol) at −20° C. and the reaction mixture was stirred at thistemperature for 2 hours. Aqueous ammonia (0.6 mL) was added and thereaction stirred at room temperature for 1 hour. The reaction wasquenched by the addition of water and EtOAc. The organic layer wasseparated, washed with water, brine, dried over sodium sulfate andconcentrated in vacuo. The residue was purified by silica gel columnchromatography eluting with 66% EtOAc in hexanes. The residue wasdissolved in TFA and stirred at room temperature for 30 minutes. Thereaction was concentrated in vacuo and dissolved in MeOH (5 mL), coolingto 0° C. Ethylene diamine was added drop-wise until the solution showeda basic pH. The reaction was extracted into 20% IPA in DCM, dried oversodium sulfate and concentrated in vacuo. The residue was purified usingpreparative TLC to afford the title compound (30 mg, 27%).

¹H NMR (400 MHz, DMSO-d₆): δ ppm 0.96 (t, 3H), 2.89 (q, 2H), 3.10 (s,3H), 4.90 (br m, 1H), 5.08 (br m, 1H), 6.57 (m, 1H), 6.81 (m, 1H), 7.19(m, 1H), 7.32 (m, 1H), 7.46 (m, 1H), 7.55-7.67 (m, 5H), 7.73 (m, 1H),7.91 (br s, 1H), 8.26 (br s, 1H), 9.86 (t, 1H), 10.05 (br s, 1H), 13.96(br s, 1H). MS m/z 575 [M+H]⁺

Example 966-(5-Fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl)-4-((2-(N-methylphenylsulfonamido)benzyl)amino)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide

The title compound was prepared according to the method described forExample 95 using6-(5-fluoro-2-(2,2,2-trifluoroethyl)-4-((2-(trimethylsilyl)ethoxy)meth-oxy)phenyl)-4-((2-(N-meth-ylphenylsulfonamido)benzyl)amino)-1-((2-(trimethylsilyl)eth-oxy)methyl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylicacid (Preparation 261). ¹H NMR (400 MHz, DMSO-d₆): δ ppm 3.10 (s, 3H),4.32 (m, 2H), 4.92 (m, 1H), 5.06 (m, 1H), 6.56 (m, 1H), 6.99 (m, 1H),7.17 (m, 1H), 7.32 (m, 1H), 7.44 (m, 1H), 7.61-7.67 (m, 6H), 7.93 (br s,1H), 8.28 (br s, 1H), 9.93 (t, 1H), 10.41 (br s, 1H), 14.04 (br s, 1H).MS m/z 630 [M+H]⁺

Example 976-(5-Fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl)-4-((5-hydroxy-2-(N-methylmethylsulfonamido)benzyl)amino)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide

To a solution of6-(5-fluoro-4-methoxy-2-(2,2,2-trifluoroethyl)phenyl)-4-((5-methoxy-2-(N-methylmethylsulfonamido)benzyl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo-[3,4-d]pyrimidine-3-carboxylicacid (Preparation 269, 0.1 g, 0.13 mmol), HOBT (36 mg, 0.27 mmol) andEDCl (51 mg, 0.27 mmol) in dichloromethane (6 mL) at 0° C. was addedammonium chloride (36 mg, 0.67 mmol) and DIPEA (0.12 mL, 0.67 mmol) andthe reaction was stirred at room temperature for 14 hours. The reactionwas concentrated in vacuo and the residue diluted with ethyl acetate.The organic solution was washed with brine, dried over sodium sulfateand concentrated in vacuo. The residue was purified using silica gelcolumn chromatography eluting with 52% EtOAc in hexanes. The residue (62mg, 0.084 mmol) was dissolved in DCM (5 mL) at 0° C. and borontribromide (0.08 mL, 0.83 mmol) was added. The reaction was stirred atroom temperature for 1 hour. The reaction was concentrated in vacuo,diluted with methanol (5 ml) and treated with ethylene diamine until thepH was basic, stirring for 1 hour. The solvent was removed in vacuo andthe residue was partitioned between ethyl acetate and water, the organicextracts were dried over sodium sulfate and purified by Preparative TLCto afford the title compound as an off-white solid (25 mg, 51%). ¹H NMR(400 MHz, DMSO-d₆): δ ppm 3.01 (s, 3H), 3.12 (s, 3H), 4.30 (m, 2H), 4.80(m, 1H), 4.91 (m, 1H), 6.68-6.71 (m, 1H), 6.76-6.77 (m, 1H), 6.97-7.00(m, 1H), 7.31-7.33 (m, 1H), 7.69-7.72 (m, 1H), 7.93 (br s, 1H), 8.28 (brs, 1H), 9.61 (br s, 1H), 9.87 (t, 1H), 10.40 (br s, 1H). MS m/z 584[M+H]⁺

Example 986-(5-Fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl)-4-((2-(N-methylmethylsulfonamido)benzyl)amino)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide

The title compound was prepared according to the method described byExample 97 using6-(5-fluoro-4-methoxy-2-(2,2,2-trifluoroethyl)phenyl)-4-((2-(N-methylmethylsulfonamido)-benzyl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylicacid (Preparation 270). ¹H NMR (400 MHz, DMSO-d₆): δ ppm 3.07 (s, 3H),3.18 (s, 3H), 4.29 (m, 2H), 4.88-5.00 (br m, 2H), 6.98 (m, 1H),7.32-7.43 (m, 3H), 7.54 (m, 1H), 7.68 (m, 1H), 7.92 (br s, 1H), 8.27 (brs, 1H), 9.92 (t, 1H), 10.39 (br s, 1H), 14.02 (br s, 1H). MS m/z 568[M+H]⁺

Example 996-(5-Fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl)-4-((5-hydroxy-2-(N-methylmethylsulfonamido)benzyl)amino)-N-(6-((2-hydroxyethyl)amino)pyridin-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide

To a solution of6-(5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl)-4-((5-hydroxy-2-(N-methylmethylsulfonamido)benzyl)amino)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylicacid (Example 174, 160 mg, 0.27 mmol) and2-[(5-aminopyridin-2-yl)amino]ethanol (84 mg, 0.54 mmol) in DMF (5 mL)was added HATU (312 mg, 0.82 mmol) and DIPEA (0.12 mL, 0.68 mmol) andthe reaction was stirred at room temperature for 18 hours. The reactionwas purified directly by Preparative HPLC to afford the title compound(48 mg, 24%). ¹H NMR (400 MHz, DMSO-d₆): δ ppm 3.02 (s, 3H), 3.12 (s,3H), 3.32 (m, 2H), 3.51 (m, 2H), 4.30 (m, 2H), 4.81-4.93 (m, 2H),6.44-6.52 (m, 2H), 6.68 (m, 1H), 6.76 (m, 1H), 6.97 (m, 1H), 7.33 (m,1H), 7.69-7.77 (m, 2H), 8.31 (d, 1H), 9.63 (t, 1H), 10.53 (br s, 1H). MSm/z 720 [M+H]⁺

Example 1006-(5-Fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl)-N-methyl-4-(((3-(N-methylmethylsulfonamido)pyrazin-2-yl)methyl)amino)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide

To a solution ofN-(3-(((6-(5-fluoro-4-methoxy-2-(2,2,2-trifluoroethyl)phenyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)methyl)pyrazin-2-yl)-N-methylmethanesulfonamide(Preparation 277, 220 mg, 0.33 mmol) in methylamine in THF (3 mL) wasadded molybdenum hexacarbonyl (87.77 mg, 0.33 mmol), Pd(OAc)₂ (5.18 mg,0.07 mmol) and DBU (0.15 mL, 0.99 mmol) and the reaction was heated to100° C. under microwave irradiation for 10 minutes. The reaction wascooled, concentrated in vacuo and purified using silica gel columnchromatography followed by preparative TLC. The residue was dissolved inDCM (5 mL) and treated with boron tribromide (0.11 mL, 1.17 mmol) at 0°C. and stirred at room temperature for 18 hours. The reaction wasconcentrated in vacuo and partitioned between DCM and saturated aqueoussodium bicarbonate solution. The organic layer was collected, washedwith brine, dried over sodium sulfate and concentrated in vacuo. Theresidue was purified using preparative TLC eluting with 5% MeOH in DCMto afford the title compound as a white solid (23 mg, 47%). ¹H NMR (400MHz, DMSO-d₆): δ ppm 2.84 (s, 3H), 3.15 (s, 3H), 3.19 (s, 3H), 4.21 (m,2H), 5.13 (m, 2H), 6.97 (m, 1H), 7.58 (m, 1H), 8.53 (d, 1H), 8.63 (d,1H), 8.86 (m, 1H), 10.06 (m, 1H), 10.37 (br s, 1H), 14.04 (br s, 1H). MSm/z 584 [M+H]⁺

The following Examples (Examples 101-104) were prepared according to themethod described for Example 1 using the appropriate pyrazolo-pyrimidineas described below:

Ex Name Data 101 6-(5-fluoro-4-hydroxy- MS m/z 598 [M + H]⁺2-(2,2,2-trifluoroeth- ¹H NMR (400 MHz, DMSO-d₆): δ ppm 3.10yl)phenyl)-4-((2-(N-(2- (s, 3H), 3.30-3.39 (m, 2H), 3.64 (m, 2H), 4.26(m, hydroxyethyl)methylsul- 2H), 4.81 (m, 1H), 4.94 (m, 2H), 6.99 (m,1H), 7.39 fonamido)benzyl)amino)- (m, 3H), 7.51 (m, 1H), 7.68 (m, 1H),7.90 (m, 1H), 1H-pyrazolo[3,4- 8.26 (m, 1H), 9.89 (s, 1H), 10.32 (br s,1H), 14.01 d]pyrimidine-3- (br s, 1H). carboxamide UsingN-(2-(((6-(4-((tert-butyldimethylsilyl)oxy)-5-fluoro-2-(2,2,2-trifluoroethyl)phenyl)-3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)methyl)phenyl)-N-(2-((tert-butyldimethylsilyl)oxy)ethyl)methanesulfonamide (Preparation 265) withammonia in THF. 102 6-(5-fluoro-4-hydroxy- MS m/z 612 [M + H]⁺2-(2,2,2-trifluoroeth- ¹H NMR (400 MHz, DMSO-d₆): δ ppm 2.83 (m, 3H),yl)phenyl)-4-((2-(N-(2- 3.10 (s, 3H), 3.33-3.40 (m, 2H), 3.64 (m, 2H),4.21- hydroxyethyl)methylsul- 4.30 (m, 2H), 4.85 (t, 1H), 5.01 (m, 2H),6.96 (m, fonamido)benzyl)amino)- 1H), 7.36-7.38 (m, 3H), 7.51 (m, 1H),7.67 (m, 1H), N-methyl-1H-pyrazolo[3,4- 8.88 (m, 1H), 9.87 (t, 1H),10.40 (br s, 1H). d]pyrimidine-3- UsingN-(2-(((6-(4-((tert-butyldimethylsilyl)oxy)-5- carboxamidefluoro-2-(2,2,2-trifluoroethyl)phenyl)-3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)methyl)phenyl)-N-(2-((tert-butyldimethylsilyl)oxy)ethyl)methanesulfonamide (Preparation 265). 1034-((2-(N-ethylmethyl- MS m/z 594 [M − H]⁻ sulfonamido)-benzyl)ami- ¹HNMR (400 MHz, DMSO-d₆): δ ppm 1.00 (t, 3H), no)-6-(5-fluoro-4-hydroxy-2.83 (d, 3H), 3.06 (s, 3H), 3.55 (m, 1H), 3.69 (m,2-(2,2,2-trifluoroeth- 1H), 4.18 (m, 2H), 4.87 (m, 1H), 4.92 (m, 1H),6.96 yl)phenyl)-N-methyl- (m, 1H), 7.33-7.40 (m, 3H), 7.51 (m, 1H), 7.65(m, 1H-pyrazolo[3,4- 1H), 8.88 (t, 1H), 9.91 (t, 1H), 10.36 (br s, 1H),d]pyrimidine-3- 14.05 (br s, 1H). carboxamide UsingN-ethyl-N-(2-(((6-(5-fluoro-2-(2,2,2-trifluoro-ethyl)-4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-3-iodo-1-((2-(trimethylsilyl)ethoxy)-methyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)methyl)phe- nyl)methanesulfonamide(Preparation 263). 104 4-((5-fluoro-2-(N- MS m/z 600 [M + H]+methylmethylsulfon- 1H NMR (400 MHz, DMSO-d6): δ ppm 2.85 (d, 3H),amido)benzyl)amino)- 3.08 (s, 3H), 3.16 (s, 3H), 4.21 (m, 2H), 4.91-4.996-(5-fluoro-4-hydroxy- (m, 2H), 6.95 (m, 1H), 7.10-7.22 (m, 2H),7.60-7.66 2-(2,2,2-trifluoroeth- (m, 2H), 8.89 (m, 1H), 9.92 (t, 1H).yl)phenyl)-N-methyl- UsingN-(4-fluoro-2-(((6-(5-fluoro-4-methoxy-2-(2,2,2- 1H-pyrazolo[3,4-trifluoroethyl)-phenyl)-3-iodo-1-((2-(trimethylsilyl)- d]pyrimidine-3-ethoxy)methyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)ami- carboxamideno)methyl)phenyl)-N-methylmethanesulfonamide (Preparation 268).

Example 1054-((2-(N-Ethylphenylsulfonamido)-5-hydroxybenzyl)amino)-6-(5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl)-N-methyl-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide

The title compound was prepared according to the method described forExample 32 usingN-ethyl-N-(2-(((6-(5-fluoro-4-methoxy-2-(2,2,2-trifluoroethyl)phenyl)-3-iodo-1-((2-(trimethyl-silyl)ethoxy)methyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)-methyl)-4-methoxyphenyl)-benzenesulfonamide(Preparation 266). ¹H NMR (400 MHz, DMSO-d₆): δ ppm 0.93 (t, 3H), 2.85(d, 3H), 3.24 (m, 1H), 3.77 (m, 1H), 4.29 (m, 2H), 4.85-4.93 (m, 2H),6.36 (m, 1H), 6.54 (m, 1H), 6.76 (m, 1H), 6.98 (m, 1H), 7.58-7.72 (m,5H), 8.89 (m, 1H), 9.62 (s, 1H), 9.85 (br s, 1H), 10.10 (br s, 1H),14.10 (br s, 1H). MS m/z 672 [M−H]⁻

Example 1064-((2-(N-Methylphenylsulfonamido)-5-hydroxybenzyl)amino)-6-(5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl)-N-methyl-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide

The title compound was prepared according to the method described forExample 32 usingN-methyl-N-(2-(((6-(5-fluoro-4-methoxy-2-(2,2,2-trifluoroethyl)phenyl)-3-iodo-1-((2-(trimethyl-silyl)ethoxy)methyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-amino)methyl)-4-methoxyphenyl)-benzenesulfonamide(Preparation 267). ¹H NMR (400 MHz, DMSO-dc): δ ppm 2.85 (s, 3H), 3.05(s, 3H), 4.34 (m, 2H), 4.86 (m, 1H), 4.97 (m, 1H), 6.32 (m, 1H), 6.51(m, 1H), 6.76 (m, 1H), 6.98 (m, 1H), 7.60-7.74 (m, 6H), 8.91 (m, 1H),9.63 (s, 1H), 9.89 (t, 1H), 10.40 (br s, 1H), 14.10 (br s, 1H). MS m/z660 [M+H]⁺

The following Examples (Examples 107-108) were prepared according to themethod described for Example 41 using the appropriatepyrazolo-pyrimidine as described below:

Ex Name Data 107 4-((2-(N-ethylphenyl- MS m/z 660 [M + H]⁺sulfonamido)-5-hydroxy- ¹H NMR (400 MHz, DMSO-d₆): δ ppm 0.94 (t, 3H),benzyl)amino)-6-(5- 3.20 (m, 1H), 3.78 (m, 1H), 4.24-4.30 (m, 2H), 4.81fluoro-4-hydroxy-2- (m, 1H), 4.97 (m, 1H), 6.35 (m, 1H), 6.53 (m, 1H),(2,2,2-trifluoroeth- 6.79 (m, 1H), 7.00 (m, 1H), 7.57-7.72 (m, 6H), 7.95yl)phenyl)-1H- (br s, 1H), 8.30 (br s, 1H), 9.63 (s, 1H), 9.87 (t, 1H),pyrazolo[3,4- 10.37 (br s, 1H), 14.05 (br s, 1H). d]pyrimidine-3- Using4-((2-(N-ethylphenylsulfon-amido)-5-methoxy- carboxamidebenzyl)amino)-6-(5-fluoro-4-methoxy-2-(2,2,2-trifluoro-ethyl)phenyl)-1-((2-(trimethylsilyl)-ethoxy)methyl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide (Preparation 253). 1084-((2-(N-methylphenyl- MS m/z 646 [M + H]⁺ sulfonamido)-5-hydroxy- ¹HNMR (400 MHz, DMSO-d₆): δ ppm 3.05 (s, 3H), benzyl)amino)-6-(5- 4.08 (m,2H), 4.82 (m, 1H), 4.96 (m, 1H), 6.32 (m, fluoro-4-hydroxy-2- 1H), 6.50(m, 1H), 6.78 (m, 1H), 7.01 (m, 1H), 7.60- (2,2,2-trifluoroeth- 7.75 (m,6H), 7.95 (br s, 1H), 8.30 (br s, 1H), 9.63 yl)phenyl)-1H- (s, 1H), 9.89(t, 1H), 10.38 (s, 1H), 14.05 (br s, 1H). pyrazolo[3,4- Using4-((2-(N-methylphenylsulfonamido)-5-methoxy- d]pyrimidine-3-benzyl)amino)-6-(5-fluoro-4-methoxy-2-(2,2,2-trifluoro- carboxamideethyl)-phenyl)-1-((2-(trimethylsilyl)-ethoxy)methyl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide (Preparation 254).

Example 1096-(5-Fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl)-N-methyl-4-((2-(methyl(sulfamoyl)amino)benzyl)amino)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide

To a solution of tert-butyl6-(5-fluoro-4-methoxy-2-(2,2,2-trifluoroethyl)phenyl)-4-((2-(methylamino)benzyl)amino)-3-(methylcarbamoyl)-1H-pyrazolo[3,4-d]pyrimidine-1-carboxylate(Preparation 256, 50 mg, 0.08 mmol) in anhydrous THF (5 mL) was addedsodium hydride (3 mg, 0.08 mmol) at 0° C. The reaction was stirred for10 minutes before the addition of sulfamoyl chloride (7 mg, 0.06 mmol)and further stirring at 0° C. for 2.5 hours. The reaction was quenchedby the addition of ice-water and extracted into EtOAc. The organic layerwas washed with brine, dried over sodium sulfate and concentrated invacuo. The residue was purified by preparative TLC and dissolved in DCM(5 mL). The solution was treated with boron tribromide (0.08 mL, 0.8mmol) and stirred at room temperature for 18 hours. The reaction wasconcentrated in vacuo and partitioned between DCM and saturated aqueoussodium bicarbonate solution. The organic layer was washed with brine,dried over sodium sulfate and concentrated in vacuo. The residue waspurified by preparative TLC to afford the title compound as a whitesolid (11 mg, 32%). ¹H NMR (400 MHz, DMSO-d₆): δ ppm 2.86 (s, 3H), 3.08(s, 3H), 4.29 (m, 2H), 4.86-5.05 (m, 2H), 6.97 (m, 1H), 7.09 (s, 2H),7.25-7.35 (m, 3H), 7.46 (m, 1H), 7.69-7.72 (m, 1H), 8.88 (t, 1H), 9.88(t, 1H), 10.37 (s, 1H), 14.02 (s, 1H). MS m/z 583 [M+H]⁺

Example 1106-(5-Fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl)-N-methyl-4-((2-(methyl(N-methylsulfamoyl)amino)benzyl)amino)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide

To a solution of tert-butyl6-(4-((tert-butoxycarbonyl)oxy)-5-fluoro-2-(2,2,2-trifluoroethyl)phenyl)-4-((2-(methylamino)benzyl)amino)-3-(methylcarbamoyl)-1H-pyrazolo-[3,4-d]pyrimidine-1-carboxylate(Preparation 255, 56 mg, 0.08 mmol) in THF (3 mL) was added sodiumhydride (2 mg, 0.08 mmol) at 0° C. The reaction was stirred at roomtemperature for 2 minutes before the addition of methanesulfonylchloride (10 mg, 0.08 mmol) and further stirring for 18 hours. Thereaction was quenched by the addition of ice-water and extracted intoEtOAc. The organic layer was washed with brine, dried over sodiumsulfate and concentrated in vacuo. The residue was purified bypreparative TLC and treated with 4M HCl in dioxane (0.3 mL). Thereaction was stirred at room temperature for 3 hours beforeconcentrating in vacuo and triturating with pentane-ether to afford thetitle compound. ¹H NMR (400 MHz, DMSO-d₆): δ ppm 2.62 (d, 3H), 2.86 (d,3H), 3.05 (s, 3H), 4.33 (m, 2H), 4.95 (m, 2H), 6.98 (m, 1H), 7.28-7.49(m, 4H), 7.73 (m, 1H), 8.89 (t, 1H), 9.92 (t, 1H), 10.38 (s, 1H), 14.03(s, 1H). MS m/z 595 [M−H]⁻

Library Protocol 1

A 0.1 M solution of6-(2-ethyl-4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-c]pyridin-4-yltrifluoromethanesulfonate (Preparation 328, 700 μL, 70 μmol) in toluenewas added to an amine of formula (XII) (200 μmol, 2.9 eq) and thesolution degassed with nitrogen. Cesium carbonate (45 mg, 140 μmol) wasadded followed by Pd₂(dba)₃ (3.4 mg, 3.5 μmol) and BINAP (2.2 mg, 3.5μmol) and the reaction further degassed with nitrogen. The reaction wasshaken at 80° C. for 16 hours before concentrating in vacuo. Water (1mL) was added followed by EtOAc (1 mL) and the mixture filtered. Theorganic layer was collected, dried over sodium sulfate and concentratedin vacuo. To the residue was added a solution of cHCl in EtOH (1 mL, v:v1:6) and the reaction shaken at 80° C. for 2 hours. The reaction wascooled, concentrated in vacuo and purified using one of the PreparativeHPLC methods described below:

Preparative HPLC

Method A: Agella Venusil ASB C18, 150×21.2 mm×5 μm; Acetonitrile-Water(0.225% formic acid); Flow rate: 35 mL/min; Gradient time 8 mins.

Method B: Boston Symmetrix ODS-H, 150×30 mm×5 μm; Acetonitrile-Water(0.225% formic acid); Flow rate: 30 mL/min; Gradient time 10 mins.

Method C: DIKMA Diamonsil(2) C18, 200×20 mm×5 μm; Acetonitrile-Water(0.225% formic acid); Flow rate: 30 mL/min; Gradient time 10 mins.

LCMS:

Method 1

A: 0.0375% TFA in water; B: 0.01875% TFA in MeCN; Column: XBridge C18,2.1×50 mm×5 μm; Gradient: From 99% [A] and 1% [B] to 95% [A] and 5% [B]in 0.6 min, further to 100% [B] in 4.0 min and finally back to initialcondition in 4.3 min, 0.8 mL/min flow rate.

Method 2

A: 0.0375% TFA in water; B: 0.01875% TFA in MeCN; Column: XBridge C18,2.1×50 mm×5 μm; Gradient: From 90% [A] and 10% [B] to 100% [B] in 4 minand finally back to initial condition in 4.3 min, 0.8 mL/min flow rate.

Method 3

A: 0.0375% TFA in water; B: 0.01875% TFA in MeCN; Column: XBridge C18,2.1×50 mm×5 μm; Gradient: From 75% [A] and 25% [B] to 100% [B] in 3.5min and finally back to initial condition in 4.0 min, 0.8 mL/min flowrate.

The compounds of the Examples in the table below (Examples 111-124) wereprepared and purified from6-(2-ethyl-4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-c]pyridin-4-yltrifluoromethanesulfonate (Preparation 328) and the appropriate amineaccording to Library Protocol 1. The compounds were isolated as theirformate salts.

Ex Name MS Data/HPLC Organic gradient/Amine 111 4-[4-(7,8-dimethoxy-3,4-MS m/z 431 [M + H]⁺ dihydroisoquinolin-2(1H)- Rt = 1.72 minyl)-1H-pyrazolo[4,3- HPLC organic gradient: 21-51%. c]pyridin-6-yl]-3-1,2,3,4-tetrahydro-7,8-dimethoxy-isoquinoline ethylphenol formate (Chem.& Pharm. Bull. (1998), 46 (6), 918-927). 112 3-ethyl-4-[4-(3- MS m/z 387[M + H]⁺ phenoxyazetidin-1-yl)-1H- Rt = 1.73 minpyrazolo[4,3-c]pyridin-6- HPLC organic gradient: 21-51%. yl]phenolformate 3-phenoxyazetidine. 113 3-ethyl-4-{4-[6-(4-methyl- MS m/z 451[M + H]⁺ 1H-imidazol-1-yl)-3,4- Rt = 2.16 min dihydroisoquinolin-2(1H)-HPLC organic gradient: 3-33%. yl]-1H-pyrazolo[4,3-6-(4-methyl-1H-imidazol-1-yl)-1,2,3,4- c]pyridin-6-yl}phenoltetrahydroisoquinoline hydrochloride formate (Preparation 345). 1143-ethyl-4-{4-[6-(2- MS m/z 445 [M + H]⁺ methoxyethoxy)-3,4- Rt = 2.64min dihydroisoquinolin-2(1H)- HPLC organic gradient: 18-48%.yl]-1H-pyrazolo[4,3- 1,2,3,4-tetrahydro-6-(2-methoxyethoxy)-c]pyridin-6-yl}phenol isoquinoline. formate 115 1-[6-(2-ethyl-4- MS m/z325 [M + H]⁺ hydroxyphenyl)-1H- Rt = 2.11 min pyrazolo[4,3-c]pyridin-4-HPLC organic gradient: 3-33%. yl]-3-methylazetidin-3-ol3-methyl-3-azetidinol (J. Med. Chem. (2010), formate 53(9), 3645-3674).116 2-[6-(2-ethyl-4- MS m/z 547 [M + H]⁺ hydroxyphenyl)-1H- Rt = 2.22min pyrazolo[4,3-c]pyridin-4- HPLC organic gradient: 6-36%.yl]-N-[2-(pyrrolidin-1- N-(2-(pyrrolidin-1-yl)ethyl)-1,2,3,4-yl)ethyl]-1,2,3,4- tetrahydroisoquinoline-7-sulfonamidetetrahydroisoquinoline-7- (Preparation 346). sulfonamide formate 117N-benzyl-2-[6-(2-ethyl-4- MS m/z 504 [M + H]⁺ hydroxyphenyl)-1H- Rt =2.50 min pyrazolo[4,3-c]pyridin-4- HPLC organic gradient: 20-50%.yl]-1,2,3,4- N-benzyl-1,2,3,4-tetrahydroisoquinoline-5-tetrahydroisoquinoline-5- carboxamide hydrochloride (Preparation 347).carboxamide formate 118 4-{4-[7-(benzyloxy)-6- MS m/z 507 [M + H]⁺methoxy-3,4- Rt = 2.20 min dihydroisoquinolin-2(1H)- HPLC organicgradient: 26-56%. yl]-1H-pyrazolo[4,3-1,2,3,4-tetrahydro-6-methoxy-7-(phenylmethoxy)- c]pyridin-6-yl}-3-isoquinoline (Heterocycles (1989), 28(1), 295-301). ethylphenol formate119 4-[4-(5-chloro-3,4- MS m/z 405 [M + H]⁺ dihydroisoquinolin-2(1H)- Rt= 2.60 min yl)-1H-pyrazolo[4,3- HPLC organic gradient: 22-52%.c]pyridin-6-yl]-3- 1,2,3,4-tetrahydro-5-chloro-isoquinoline. ethylphenolformate 120 4-chloro-3-({1-[6-(2-ethyl- MS m/z 446 [M + H]⁺4-hydroxyphenyl)-1H- Rt = 2.56 min pyrazolo[4,3-c]pyridin-4- HPLCorganic gradient: 21-51%. yl]azetidin-3-yl}oxy)benzo-3-(azetidin-3-yloxy)-4-chlorobenzonitrile nitrile formate hydrochloride(Preparation 348). 121 3-ethyl-4-[4-(6-fluoro-3,4- MS m/z 389 [M + H]⁺dihydroisoquinolin-2(1H)- Rt = 2.70 min yl)-1H-pyrazolo[4,3- HPLCorganic gradient: 19-49%. c]pyridin-6-yl]phenol1,2,3,4-tetrahydro-6-fluoro-isoquinoline. formate 1223-ethyl-4-[4-(8-methoxy- MS m/z 401 [M + H]⁺ 3,4-dihydroisoquinolin- Rt= 1.82 min 2(1H)-yl)-1H-pyrazolo[4,3- HPLC organic gradient: 14-44%.c]pyridin-6-yl]phenol 1,2,3,4-tetrahydro-8-methoxyisoquinoline. formate123 N-{2-[6-(2-ethyl-4- MS m/z 464 [M + H]⁺ hydroxyphenyl)-1H- Rt = 2.16min pyrazolo[4,3-c]pyridin-4- HPLC organic gradient: 13-43%.yl]-1,2,3,4- N-1,2,3,4-tetrahydroisoquinolin-5- tetrahydroisoquinolin-5-yl}methanesulfonamide hydrochloride. yl}methanesulfonamide formate 1244-(4-{[2-(biphenyl-4- MS m/z 435 [M + H]⁺ yl)ethyl]amino}-1H- Rt = 2.20min pyrazolo[4,3-c]pyridin-6- HPLC organic gradient: 25-55%.yl)-3-ethylphenol formate 2-([1,1′-biphenyl]-4-yl)ethanamine.

Example 125N-[2-({[6-(2-Ethyl-4-hydroxyphenyl)-1H-pyrazolo[4,3-c]pyridin-4-yl]amino}methyl)phenyl]-N-methylmethanesulfonamidehydrochloride

To a solution of6-(2-ethyl-4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-1-((2-(trimethyl-silyl)ethoxy)methyl)-1H-pyrazolo[4,3-c]pyridin-4-yltrifluoromethanesulfonate (Preparation 328, 14 mg, 0.02 mmol) in toluene(0.5 mL) was added N-[2-aminomethyl)phenyl]-N-methylmethanesulfonamide(WO20101058846A1, 9 mg, 0.03 mmol), cesium carbonate (14 mg, 0.04 mmol),Pd(OAc)₂ (0.9 mg, 0.004 mmol) and BINAP (3.7 mg, 0.006 mmol). Thereaction was degassed with nitrogen followed by heating to 150° C. undermicrowave irradiation for 15 minutes. The reaction was filtered, washingthrough with DCM and the filtrate concentrated in vacuo. The residue waspurified using silica gel column chromatography eluting with 1-5% MeOHin DCM. The residue was dissolved in MeOH (1 mL) and cHCl (0.2 mL) wasadded and the reaction heated to 80° C. for 3 hours. The reaction wascooled, concentrated in vacuo and triturated with DCM to afford thetitle compound as the hydrochloride salt (10 mg, 50%). ¹H NMR (400 MHz,DMSO-d₆): δ ppm 0.75 (t, 3H), 2.40 (q, 2H), 3.00 (s, 3H), 3.03 (s, 3H),4.55 (br m, 1H), 4.95 (br m, 1H), 6.50 (m, 3H), 7.00 (m, 1H), 7.25 (m,2H), 7.40-7.50 (m, 2H), 7.80 (t, 1H), 8.20 (s, 1H), 9.25 (s, 1H), 12.95(s, 1H). MS m/z 452 [M+H]⁺

The following compounds of the Examples below (Examples 126-130) wereprepared according to the method described for Example 125 above using6-(2-ethyl-4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-c]pyridin-4-yltrifluoromethanesulfonate (Preparation 328) or6-(2-ethyl-5-fluoro-4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-c]pyridin-4-yltrifluoromethanesulfonate (Preparation 331) or6-(2-ethyl-5-fluoro-4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridin-4-yltrifluoromethanesuffonate (Preparation 330) and the appropriate amine.Purification took place according to the Purification Method (PM)described or one of the following below. Compounds were isolated as thefree parent, diethylamine salt or hydrochloride salt as described below:

Purification Method J: The residue was dissolved in DMSO (0.9 mL) andtriethylamine (0.1 mL) and purified using Preparative HPLC.

Ex Name MS Data/PM/Amine 126 Racemic 1-[6-(2-ethyl-4- MS m/z 416 [M +H]⁺ hydroxyphenyl)-1H- Rt = 2.75 min pyrazolo[4,3-c]pyridin-4- PM J.yl]-N,N- Racemic N,N-dimethyl-3-pyrrolidinesulfonamidedimethylpyrrolidine-3- hydrochloride. sulfonamide (free parent). 127N-[2-({[6-(2-ethyl-4- MS m/z 466 [M + H]⁺ hydroxyphenyl)-1H- Rt = 2.99min pyrazolo[4,3-c]pyridin-4- PM J. yl]amino}methyl)-3-N-[2-(aminomethyl)-3-methylphenyl]-N-methyl- methylphenyl]-N-methanesulfonamide (WO2012/045195A1). methylmethanesulfonamidediethylamine salt 128 3-ethyl-4-[4-(4- MS m/z 353 [M + H]⁺methoxypiperidin-1-yl)- Rt = 2.13 min 1H-pyrazolo[4,3-c]pyridin- PM J.6-yl]phenol diethylamine 4-methoxypiperidine. salt 129 N-[2-({[2-(3,4-MS m/z 634 [M + H]⁺ dimethoxyphenyl)ethyl][6- ¹H NMR (400 MHz, DMSO-d₆):δ ppm 0.85 (br s, (2-ethyl-5-fluoro-4- 3H), 2.95 (m, 2H), 3.09 (s, 6H),3.64 (s, 3H), 3.69 hydroxyphenyl)-1H- (s, 3H), 4.03 (m, 1H), 5.09 (m,2H), 6.72-6.83 (m, pyrazolo[4,3-c]pyridin-4- 3H), 6.91 (br s, 1H),7.16-7.32 (br s, 6H), 7.60 (br s, yl]amino}methyl)phenyl]- 1H), 7.98 (brs, 1H), 8.24 (br s, 1H), 9.80 (br s, 1H), N-methylmethanesulfon- 10.29(br s, 1H). amide hydrochloride N-(2-(((3,4-dimethoxyphenethyl)amino)-methyl)phenyl)-N-methylmethanesulfonamide (Preparation 367). 130N-[2-({[6-(2-ethyl-5-fluoro- MS m/z 667 [M + H]⁺ 4-hydroxyphenyl)-1H- ¹HNMR (400 MHz, DMSO-d₆): δ ppm 0.94-1.06 (m, pyrazolo[4,3-c]pyridin-4-3H), 1.75-1.88 (m, 4H), 2.66 (s, 3H), 2.71-2.81 (m,yl](2-{4-[(methylsulfo- 2H), 2.95-3.05 (s, 6H), 4.01 (m, 2H), 5.09 (m,2H), nyl)amino]phenyl}ethyl)ami- 6.90-6.98 (m, 2H), 7.09-7.11 (m, 2H),7.19-7.21 (m, no}methyl)phenyl]-N- 2H), 7.29-7.37 (m, 3H), 7.42-7.60 (m,1H), 9.61 (s, methylmethanesulfonamide 1H). hydrochlorideN-methyl-N-(2-(((4-(methylsulfonamido)- phenethyl)amino)methyl)phenyl)methane- sulfonamide (Preparation 369).

Example 131N-[2-({[6-(2-Ethyl-5-fluoro-4-hydroxyphenyl)-1H-pyrazolo[4,3-c]pyridin-4-yl]amino}methyl)phenyl]-N-methylmethanesulfonamide

To a stirring solution of 4-nitrophenyl{2-[methyl(methyl-sulfonyl)amino]benzyl}carbamate (Preparation 166, 2.02g, 5.32 mmol) and triethylamine (2.12 mL, 15.33 mmol) in anhydrous DMF(20 mL) was added6-(2-ethyl-5-fluoro-4-{[2-(trimethylsilyl)ethoxy]methoxy}phenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine5-oxide (Preparation 332, 1.5 g, 3.07 mmol) and the reaction was heatedto 80° C. for 15 hours. The reaction was concentrated in vacuo andpartitioned between water and ethyl acetate. The organic layer waswashed with brine, dried over sodium sulfate and concentrated in vacuo.The residue was purified by silica gel column chromatography elutingwith 1% MeOH in DCM. The residue was dissolved in MeOH (10 mL) and cHCl(8 mL) was added. The reaction was heated at from 65-80° C. for 6 hoursbefore cooling and concentrating in vacuo. The residue was trituratedwith MeCN/ether to afford the title compound as the hydrochloride salt(400 mg, 42%). ¹H NMR (400 MHz, DMSO-d₆): δ ppm 0.98 (m, 3H), 2.32-2.41(m, 2H), 3.09-3.18 (m, 6H), 5.11 (m, 2H), 6.98 (s, 2H), 7.09-7.21 (m,2H), 7.21 (s, 2H), 7.27 (br s, 21H), 7.34-7.36 (m, 1H), 7.42-7.48 (m,3H), 7.63 (br s, 1H), 8.70 (br s, 1H), 10.04 (br s, 1H), 10.35 (br s,1H), 12.20 (br s, 1H), 14.17 (br s, 1H). MS m/z 470 [M+H]⁺

The following compounds of the Examples below (Examples 132-136) wereprepared according to the method described for Example 131 above using6-(2-ethyl-5-fluoro-4-{[2-(trimethylsilyl)ethoxy]methoxy}phenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine5-oxide (Preparation 332) or6-(2-ethyl-4-((2-(trimethylsilyl)-ethoxy)methoxy)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-c]pyridine5-oxide (Preparation 333) and the appropriate aminocarbamate. Thecompounds were isolated as their hydrochloride salts. Purification wascarried out according to the Purification Method (PM) described or oneof the following below:

Purification Method K: Trituration with pentane-ether.

Ex Name MS Data/PM/Aminocarbamate 132 N-[2-({[6-(2-ethyl-5-fluoro- MSm/z 484 [M + H]⁺ 4-hydroxyphenyl)-1H- ¹H NMR (400 MHz, DMSO-d₆): δ ppm1.00 (s, 3H), pyrazolo[4,3-c]pyridin-4- 2.30 (m, 5H), 3.14 (s, 6H), 4.77(m, 2H), 6.97 (s, yl]amino}methyl)-4- 2H), 7.21 (d, 2H), 7.33 (d, 1H),7.45 s, 1H), 8.68 (s, methylphenyl]-N- 1H), 9.94 (s, 1H), 10.33 (s, 1H),12.17 (s, 1H), 14.16 methylmethanesulfonamide (s, 1H). hydrochloride PMK. 4-nitrophenyl {5-methyl-2-[methyl(methylsulfo-nyl)amino]benzyl}carbamate (Preparation 165). 133 N-[4-chloro-2-({[6-(2-MS m/z 504 [M + H]⁺ ethyl-5-fluoro-4- ¹H NMR (400 MHz, DMSO-d₆): δ ppm0.87 (t, 3H), hydroxyphenyl)-1H- 3.01 (s, 3H), 3.24 (s, 3H), 4.85-5.07(br s, 4H), 6.87 pyrazolo[4,3-c]pyridin-4- (s, 1H), 6.93 (d, 1H), 7.13(d, 1H), 7.45 (d, 1H), 7.53- yl]amino}methyl)phenyl]- 7.59 (m, 2H), 8.48(s, 1H), 9.96 (br s, 1H), 10.34 (br N-methylmethane- s, 1H), 12.32 (brs, 1H), 14.15 (br s, 1H). sulfonamide4-nitrophenyl{5-chloro-2-[methyl(methylsulfonyl)- hydrochlorideamino]benzyl}carbamate (Preparation 156) 134N-[2-({[6-(2-ethyl-5-fluoro- MS m/z 488 [M + H]⁺ 4-hydroxyphenyl)-1H- ¹HNMR (400 MHz, DMSO-d₆): δ ppm 1.05 (t, 3H), pyrazolo[4,3-c]pyridin-4-2.49 (s, 2H), 3.05 (s, 3H), 3.21 (s, 3H), 4.94 (s, 2H),yl]amino}methyl)-3- 6.98 (t, 2H), 7.27 (d, 1H), 7.36 (t, 1H), 7.52 (m,2H), fluorophenyl]-N- 8.72 (s, 1H), 10.38 (s, 1H), 12.56 (s, 1H).methylmethanesulfon- 4-nitrophenyl{2-[ethyl(methylsulfonyl)amino]- amidehydrochloride benzyl}carbamate (Preparation 162). 135N-[2-({[6-(2-ethyl-5-fluoro- MS m/z 488 [M + H]⁺ 4-hydroxyphenyl)-1H- ¹HNMR (400 MHz, DMSO-d₆): δ ppm 0.98 (m, 3H), pyrazolo[4,3-c]pyridin-4-1.25 (m, 3H), 2.39-2.41 (m, 1H), 2.53 (s, 1H), 3.20yl]amino}methyl)phenyl]- (m, 1H), 5.08-5.10 (m, 2H), 6.99 (m, 2H), 7.27(s, N-methylethane- 1H), 7.43-7.47 (m, 3H), 7.61 (m, 1H), 8.65 (br s,1H), sulfonamide 10.01 (s, 1H), 10.32 (br s, 1H), 12.15 (br s, 1H),hydrochloride 13.01 (br s, 1H), 14.22 (br s, 1H).4-nitrophenyl{2-[(ethylsulfonyl)(methyl)- amino]benzyl}carbamate(Preparation 159). 136 N-ethyl-N-[2-({[6-(2-ethyl- MS m/z 498 [M + H]⁺5-fluoro-4-hydroxyphenyl)- ¹H NMR (400 MHz, DMSO-d₆): δ ppm 1.04 (m,5H), 1H-pyrazolo[4,3-c]pyridin- 1.24 (m, 1H), 2.32 (m, 1H), 3.08 (m,1H), 3.61-3.70 4-yl]amino}methyl)phe- (m, 2H), 4.94 (m, 2H), 7.00 (m,2H), 7.28 (m, 1H), nyl]ethanesulfonamide 7.39-7.56 (m, 4H), 8.30-8.61(m, 2H), 9.95 (br s, 1H), hydrochloride 10.31 (br s, 1H), 12.00 (br s,1H), 13.00 (br s, 1H), 14.15 (br s, 1H).4-nitrophenyl[ethyl(ethylsulfonyl)amino]benyl}- carbamate (Preparation157).

Example 137N-[2-({[6-(2-Ethyl-5-fluoro-4-hydroxyphenyl)-1H-pyrazolo[4,3-c]pyridin-4-yl]amino}methyl)phenyl]-N-propylmethanesulfonamide

To6-(2-ethyl-5-fluoro-4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-1-((2-(trimeth-ylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-c]pyridin-4-yltrifluoromethanesulfonate (Preparation 331, 200 mg, 0.30 mmol) andN-(2-(aminomethyl)phenyl)-N-propylmethanesulfonamide trifluoroacetate(Preparation 349, 172 mg, 0.71 mmol) in DMF (5 mL) was addedtriethylamine (0.19 mL, 1.4 mmol) and the reaction was heated 10 to 110°C. for 2 hours. The reaction was cooled and partitioned between EtOAcand water. The organic layer was collected, washed with water, driedover magnesium sulfate and concentrated in vacuo. The residue waspurified using silica gel column chromatography eluting with 1:1EtOAc:Heptanes. The residue was dissolved in MeOH (5 mL) and cHCl (1.5mL) was added and the reaction heated to 60° C. for 18 hours. Thereaction was cooled, concentrated in vacuo and purified usingpreparative HPLC to afford the title compound as the free parent.Rt=2.85 minutes; MS m/z 498 [M+H]⁺

The following compounds of the Examples below (Examples 138-144) wereprepared according to the method described for Example 137 above using6-(2-ethyl-5-fluoro-4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo-[4,3-c]pyridin-4-yltrifluoromethanesulfonate (Preparation 331) and the appropriate amine.Deprotection was carried out as described or using TFA/TES in place ofcHCl. Purification was carried out according to the Purification Method(PM) described or one of the following below. The compounds were allisolated as free parents.

Purification Method L: The reaction mixture was quenched by the additionof saturated aqueous NaHCO₃ solution and extracted into DCM. The organiclayer was collected, dried over sodium sulfate and concentrated invacuo. The residue was purified using preparative HPLC.

Ex Name MS Data/PM/Amine 138 N-ethyl-N-[2-({[6-(2-ethyl-5- MS m/z 484[M + H]⁺ fluoro-4-hydroxyphenyl)- Rt = 2.75 min1H-pyrazolo[4,3-c]pyridin- N-[2-(aminomethyl)phenyl]-N-4-yl]amino}methyl)phe- ethylmethanesulfonamide hydrochloridenyl]methanesulfonamide (Preparation 188). 139N-butyl-N-[2-({[6-(2-ethyl-5- MS m/z 512 [M + H]⁺fluoro-4-hydroxyphenyl)- Rt = 2.98 min 1H-pyrazolo[4,3-c]pyridin-N-(2-(aminomethyl)phenyl)-N- 4-yl]amino}methyl)phe-butylmethanesulfonamide trifluoroacetate nyl]methanesulfonamide(Preparation 350). 140 N-[2-({[6-(2-ethyl-5-fluoro- MS m/z 583 [M + H]⁺4-hydroxyphenyl)-1H- Rt = 1.98 min pyrazolo[4,3-c]pyridin-4-N-methyl-N-(2-(((2-morpholinoethyl)ami- yl][2-(morpholin-4-no)methyl)phenyl)methanesulfonamide yl)ethyl]amino}-meth- (Preparation353). yl)phenyl]-N-methylmeth- anesulfonamide 141N-butyl-N-(2-(((6-(2-ethyl-5- MS m/z 526 [M + H]⁺fluoro-4-(I1-oxidanyl)phenyl)- Rt = 3.00 min1I2-pyrazolo[4,5-c]pyridin-4- N-butyl-N-(2-((methylamino)methyl)phenyl)-yl)(methyl)amino)methyl)phe- methanesulfonamide (Preparation 354).nyl)methanesulfonamide 142 N-ethyl-N-[2-({[6-(2-ethyl-5- MS m/z 512 [M +H]⁺ fluoro-4-hydroxyphenyl)- Rt = 2.03 min 1H-pyrazolo[4,3-c]pyridin-N-ethyl-N-(4-methyl-2-((methylamino)meth- 4-yl](methyl)amino}methyl)-yl)phenyl)methanesulfonamide 4-methylphenyl]methanesulfon- (Preparation355). amide 143 N-[2-({ethyl[6-(2-ethyl-5- MS m/z 512 [M + H]⁺fluoro-4-hydroxyphenyl)- Rt = 2.89 min 1H-pyrazolo[4,3-c]pyridin-N-(2-((ethylamino)methyl)-4-methylphenyl)-N- 4-yl]amino}methyl)-4-methylmethanesulfonamide (Preparation 356). methylphenyl]-N-methyl- PML. methanesulfonamide 144 N-[2-({[6-(2-ethyl-5-fluoro- MS m/z 526 [M +H]⁺ 4-hydroxyphenyl)-1H- Rt = 3.04 min pyrazolo[4,3-c]pyridin-4-N-methyl-N-(4-methyl-2-((propylami- yl](propyl)amino}methyl)-4-no)methyl)phenyl)methanesulfonamide methylphenyl]-N- (Preparation 357).methylmethanesulfonamide PM L.

Example 145N-Ethyl-N-[2-({[6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-pyrazolo[4,3-c]pyridin-4-yl](methyl)amino}methyl)phenyl]methanesulfonamidehydrochloride

To a solution of6-(2-ethyl-5-fluoro-4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridin-4-yltrifluoromethanesulfonate (Preparation 330, 400 mg, 0.64 mmol) andN-ethyl-N-(2-((methyl-amino)methyl)phenyl)methanesulfonamide(Preparation 358, 234 mg, 0.96 mmol) in toluene (8 mL) was added cesiumcarbonate (420 mg, 1.29 mmol) and the mixture was degassed with nitrogenfor 5 minutes. Pd(OAc)₂ (16 mg, 0.064 mmol) and BINAP (60 mg, 0.096mmol) were added and the reaction was heated to 140° C. under microwaveirradiation for 30 minutes. The reaction was partitioned between waterand ethyl acetate, the organic layer collected, washed with brine, driedover sodium sulfate, and concentrated in vacuo. The residue was purifiedusing silica gel column chromatography eluting with 36% EtOAc inhexanes. The residue (147 mg, 0.22 mmol) was dissolved in MeOH (10 mL)and cHCl (10 mL) was added with heating to 65° C. for 4 hours. Thereaction was concentrated in vacuo and triturated with pentane-ether toafford the title compound as the hydrochloride salt (125 mg, 34%). ¹HNMR (400 MHz, DMSO-d₆): δ ppm 1.00-1.13 (m, 6H), 2.56 (m, 2H), 3.07 (s,3H), 3.43 (s, 3H), 3.66 (m, 2H), 5.19 (br s, 2H), 6.82 (s, 1H), 6.88 (d,1H), 7.09 (d, 1H), 7.23 (t, 3H), 7.33 (t, 1H), 7.39 (t, 1H), 7.53 (d,1H), 8.16 (s, 1H), 10.31 (br s, 1H), 11.95 (br s, 1H), 14.16 (br s, 1H).MS m/z 496 [M−H]⁻

Example 146N-[2-({[6-(2-Ethyl-5-fluoro-4-hydroxyphenyl)-1H-pyrazolo[4,3-c]pyridin-4-yl](methyl)amino}methyl)phenyl]-N-methylmethanesulfonamidehydrochloride

The title compound was prepared according to the method described forExample 145 using6-(2-ethyl-5-fluoro-4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridin-4-yltrifluoromethanesulfonate (Preparation 330),N-methyl-N-(2-((methylamino)methyl)phenyl)methanesulfonamide(Preparation 359). The residue was triturated with pentane-ether andfurther purified by Preparative TLC to afford the title compound as thehydrochloride salt (60 mg, 59%). ¹H NMR (400 MHz, DMSO-d₆): δ ppm 0.91(m, 3H), 2.54 (m, 2H), 3.09 (s, 3H), 3.16 (s, 3H), 3.37 (s, 3H), 5.10(s, 2H), 6.67 (s, 1H), 6.79 (d, 1H), 7.01 (d, 1H), 7.09 (d, 1H), 7.28(t, 1H), 7.34 (t, 1H), 7.55 (d, 1H), 8.06 (s, 1H), 9.74 (s, 1H), 13.08(s, 1H). MS m/z 482 [M−H]⁻

Example 147N-[2-({[6-(2-Ethyl-5-fluoro-4-hydroxyphenyl)-1H-pyrazolo[4,3-c]pyridin-4-yl]amino}methyl)phenyl]-N-(2-hydroxyethyl)methanesulfonamide

To a solution ofN-(2-(benzyloxy)ethyl)-N-(2-(((6-(2-ethyl-5-fluoro-4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-c]pyridin-4-yl)amino)methyl)phenyl)methanesulfonamide(Preparation 327, 79 mg, 0.09 mmol) in 1:1 MeOH:EtOH (10 mL) was addedammonium formate (1 mg, 0.09 mmol) followed by palladium hydroxide (4mg). The reaction was heated to 70° C. for 18 hours before cooling andfiltering thought celite. The filtrate was concentrated in vacuo andpartitioned between EtOAc and water. The organic layer was collected,washed with water and brine, dried over sodium sulfate and concentratedin vacuo. The residue was dissolved in DCM (3 mL) and TFA (141 μL, 1.84mmol) followed by triethylsilane (21.5 μL, 0.18 mmol) were added. Thereaction was heated to 70° C. for 72 hours before cooling and quenchingwith saturated aqueous NaHCO₃ solution. The reaction was extracted intoEtOAc, and the organic layer was collected, dried over sodium sulfateand concentrated in vacuo. The residue was triturated with DCM to affordthe title compound (16 mg, 43%). ¹H NMR (400 MHz, CDCl₃): δ ppm 0.90 (t,3H), 2.25-2.40 (m, 2H), 3.18 (s, 3H), 3.25 (m, 2H), 3.75-3.80 (m, 1H),3.83-3.95 (m, 1H), 4.75 (m, 1H), 5.30 (m, 1H), 6.70 (s, 1H), 6.80 (m,1H), 6.95 (m, 1H), 7.40 (m, 2H), 7.50 (m, 1H), 7.63 (m, 1H), 8.28 (s,1H). MS m/z 500 [M+H]⁺

Example 148N-{2-[({6-[5-Fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-1H-pyrazolo[4,3-c]pyridin-4-yl}amino)methyl]phenyl}-N-methylmethanesulfonamide

To a solution of6-(5-fluoro-4-methoxy-2-(2,2,2-trifluoroethyl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-c]pyridine5-oxide (Preparation 334, 100 mg, 0.21 mmol) in DCM (1 mL) was addedN-[2-(aminomethyl)phenyl]-N-methylmethanesulfonamide (WO20101058846A1,60 mg, 0.28 mmol) followed by PyBrop (130 mg, 0.28 mmol) and DIPEA (0.14mL, 0.81 mmol). The reaction was stirred at room temperature for 18hours. The reaction was poured into saturated aqueous NaHCO₃ solutionand extracted with DCM three times. The organic layers were collected,dried over sodium sulfate and concentrated in vacuo. The residue waspurified using silica gel column chromatography eluting with 1:1 EtOAcin hexanes. The residue was dissolved in DCM (0.6 mL) and TFA (0.2 mL)followed by TES (0.05 mL) were added at 0° C. The reaction was stirredat room temperature for 18 hours before being quenched with saturatedaqueous NaHCO₃ solution. The mixture was extracted into DCM, the organiclayer collected, dried over sodium sulfate and concentrated in vacuo.The residue was purified using silica gel column chromatography elutingwith 60% EtOAc in heptanes. The residue was dissolved in DCM (1 mL) andBBr₃ (0.72 mL) was added at 0° C. The reaction was stirred at roomtemperature for 18 hours before concentrating in vacuo and purifying bypreparative HPLC to afford the title compound. MS m/z 524 [M+H]⁺ Rt=2.39minutes.

Example 149N-(2-{[{6-[5-Fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-1H-pyrazolo[4,3-c]pyridin-4-yl}(methyl)amino]methyl})phenyl)-N-methylmethanesulfonamide

The title compound was prepared according to the method described forExample 148 usingN-methyl-N-(2-((methylamino)methyl)phenyl)methanesulfonamide(Preparation 359). MS m/z 538 [M+H]⁺ Rt=2.52 minutes.

Example 150N-{2-[({6-[5-Fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-1H-pyrazolo[4,3-c]pyridin-4-yl}amino)methyl]-4-methylphenyl}-N-methylmethanesulfonamide

The title compound was prepared according to the method described forExample 148 using the free base ofN-[2-(aminomethyl)-4-methylphenyl]-N-methylmethanesulfonamidehydrochloride (Preparation 189). MS m/z 538 [M+H]⁺ Rt=2.47 minutes.

Library Protocol 2

To a 0.2M solution of amines of formula (XII) (1 mL, 200 umol) in nBuOHwas added a 0.2M solution of4,6-dichloro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidine(WO20131014567A1, 1 mL, 200 umol) followed by DIPEA (120 uL, 700 umol).The reaction was heated to 80° C. for 16 hours before concentrating invacuo. The residue was dissolved in 1:1 MeOH:toluene (1.5 mL). To thesolution was added potassium carbonate (62 mg, 450 umol), Peppsi™-IPr (3mg, 4.5 umol) and(2-{[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(2,2,2-trifluoroethyl)phenoxy]methoxy}ethyl)(trimethyl)silane(Preparation 150, 400 mmol). The reaction was heated to 100° C. undermicrowave irradiation for 25 minutes before concentrating in vacuo. Theresidue was dissolved in EtOAc (5 mL) and washed with water (3 mL) andbrine (3 mL). The organic extract was dried over sodium sulfate andconcentrated in vacuo. The residue was dissolved in TFA (1 mL) andstirred at room temperature for 16 hours. The reaction was concentratedin vacuo and azeotroped with toluene. The residue was dissolved in MeOHand ethylenediamine (35 uL, 500 umol) was added with stirring at roomtemperature for 18 hours. The reaction was concentrated in vacuo,dissolved in DMSO (1 mL) and purified using preparative HPLC asdescribed below:

LCMS:

A: 0.05% formic acid in water; B: MeCN; Column: RESTEK C18, 30×2.1 mm×3μm; Gradient: From 98% [A] and 2% [B] to 90% [A] and 10% [B] in 1 min,further to 98% [B] in 2 min and finally back to initial condition in2.90 min, 1.5 mL/min flow rate.

Preparative HPLC:

Method A: Gemini NXC18 (100×20 mm×5μ); Acetonitrile-water (20 mMNH₄CO₃); Flow rate 20 mL/min; Gradient time 10 mins for 10-75% organicelution.

Method B: reprosil Gold C18 (250×20 mm×5μ); Acetonitrile-water (20 mMNH₄CO₃); Flow rate 20 mL/min; Gradient time 18 mins for 10-70% organicelution.

The compounds of the Examples in the table below (Examples 151-154) wereprepared and purified from4,6-dichloro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidine(WO20131014567A1),(2-{[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(2,2,2-trifluoroethyl)phenoxy]methoxy}ethyl)(trimethyl)silane(Preparation 150) and the appropriate amine according to LibraryProtocol 2.

Ex Name MS Data/Amine 151 4-{4-[(cyclopropylmethyl)- MS m/z 382 [M + H]⁺amino]-1H-pyrazolo[3,4- Rt = 1.53 minutes d]pyrimidin-6-yl}-2-fluoro-5-Cyclopropylmethylamine (2,2,2-trifluoroethyl)phenol 152 4-{4-[(2- MS m/z396 [M + H]⁺ cyclopropylethyl)amino]- Rt = 1.57 minutes 1H-pyrazolo[3,4-Cyclopropylethylamine d]pyrimidin-6-yl}-2-fluoro-5-(2,2,2-trifluoroethyl)phenol 153 2-fluoro-4-{4-[(2-methyl- MS m/z 384[M + H]⁺ propyl)amino]-1H- Rt = 1.56 minutes pyrazolo[3,4-d]pyrimidin-6-Isobutylamine yl}-5-(2,2,2- trifluoroethyl)phenol 1544-[4-(butylamino)-1H- MS m/z 384 [M + H]⁺ pyrazolo[3,4-d]pyrimidin-6- Rt= 1.57 minutes yl]-2-fluoro-5-(2,2,2- Butylamine trifluoroethyl)phenol

Example 155N-[2-({[6-(2-Ethyl-5-fluoro-4-hydroxyphenyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl]amino}methyl)phenyl]-N-methylmethanesulfonamidehydrochloride

The title compound was prepared according to the method described forExample 125 usingN-(2-(((6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)methyl)phenyl)-N-methylmethanesulfonamide(Preparation 312) and(2-{[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-ethyl-phenoxy]methoxy}ethyl)(trimethyl)silane (WO20131014567A1). SPhos was used as the ligand and the finalresidue was triturated with pentane/ether to afford the hydrochloridesalt. ¹H NMR (400 MHz, DMSO-d₆): δ ppm 0.91 (t, 3H), 2.66 (m, 2H), 3.06(s, 3H), 3.13 (s, 3H), 4.82 (br s, 1H), 5.06 (br s, 1H), 6.86 (d, 1H),7.33-7.46 (m, 4H), 7.55 (d, 1H), 8.55 (br s, 1H), 10.33 (br s, 1H),14.56 (br s, 1H). MS m/z 471 [M+H]⁺

Example 156N-(2-(((6-(2-Ethyl-4-hydroxy-6-methylphenyl-1H-pyrazolo[4,3-c]pyridin-4-yl)amino)methyl)phenyl)-N-methylmethanesulfonamide

The title compound was prepared according to the method described forPreparation 299 pyrimidines using2-(4-(benzyloxy)-2-ethyl-6-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(Preparation 342) followed by treating the residue with TFA at reflux.The reaction was concentrated in vacuo and partitioned between EtOAc andsaturated aqueous sodium bicarbonate solution. The organic extracts werewashed with brine, dried over sodium sulfate and concentrated in vacuo.The residue was purified by preparative HPLC. ¹H NMR (400 MHz, DMSO-d₆):δ ppm 0.63-0.82 (m, 3H), 1.86 (m, 5H), 2.91 (s, 3H), 2.94 (s, 3H), 4.37(br m, 1H), 4.85 (br m, 1H), 6.36 (br m, 3H), 7.20 (m, 2H), 7.33 (m,2H), 8.17 (m, 1H), 9.03 (m, 1H), 12.88 (br s, 1H). MS m/z 466 [M+H]⁺

Example 157

N-[2-({[6-(2-Ethyl-5-fluoro-4-hydroxyphenyl)-3-(1H-imidazol-2-yl)-1H-pyrazolo[4,3-c]pyridin-4-yl]amino}methyl)phenyl]-N-methylmethanesulfonamide

A solution ofN-[2-({[6-(2-ethyl-5-fluoro-4-{[2-(trimethylsilyl)ethoxy]methoxy}phenyl)-3-iodo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazolo[4,3-c]pyridin-4-yl]amino}methyl)phenyl]-N-methylmethanesulfonamide(Preparation 79, 200 mg, 0.22 mmol) and2-bromo-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-imidazole (J. Org. Chem.(2010) 75 (15) 4911-4920, 62.102 mg, 0.22 mmol) in toluene (2 mL) wasdegassed with nitrogen for 5 minutes. Bis(tributyltin) (0.27 mL, 0.54mmol) and copper (I) iodide (8.53 mg, 0.045 mmol) were added followed byPd(PPh₃)₄ (25.88 mg, 0.022 mmol) and the reaction was heated to 100° C.for 6.5 hours. The reaction was cooled, concentrated in vacuo andpurified using silica gel column chromatography eluting with 15% EtOAcin hexanes. The residue (80 mg, 0.086 mmol) was treated with TFA (2 mL)and the solution stirred at room temperature for 30 minutes. Thereaction was concentrated in vacuo, dissolved in MeOH (5 mL) and cooledin ice water. Ethylene diamine was added dropwise until the solution wasbasic, with stirring for 15 minutes. The solution was concentrated invacuo and purified using silica gel column chromatography eluting with60% EtOAc in hexanes to afford the title compound (25 mg, 54%). ¹H NMR(400 MHz, DMSO-d₆): δ ppm 0.91 (t, 3H), 2.43 (m, 2H), 3.06 (s, 3H), 3.10(s, 3H), 4.70 (br m, 1H), 5.00 (br m, 1H), 6.58 (m, 1H), 6.77 (m, 1H),7.05 (m, 1H), 7.10 (s, 1H), 7.26-7.31 (m, 3H), 7.47 (m, 2H), 9.74 (s,1H), 10.89 (t, 1H), 12.93 (s, 1H), 13.29 (s, 1H). MS m/z 536 [M+H]⁺

Example 158N-[2-({[3-(4,5-Dimethyl-1H-imidazol-2-yl)-6-(2-ethyl-5-fluoro-4-hydroxyphenyl-1H-pyrazolo[4,3-c]pyridin-4-yl]amino}methyl)phenyl]-N-methylmethanesulfonamide

The title compound was prepared according to the method described byExample 157 usingN-[2-({[6-(2-ethyl-5-fluoro-4-{[2-(trimethylsilyl)ethoxy]-methoxy}phenyl)-3-iodo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazolo[4,3-c]pyridin-4-yl]amino}methyl)phenyl]-N-methylmethanesulfonamide(Preparation 79) and2-bromo-4,5-dimethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole(Preparation 386) at 115° C. under microwave irradiation for 30 minutes.¹H NMR (400 MHz, DMSO-d₆): δ ppm 0.97 (t, 3H), 2.56 (m, 2H), 3.04 (s,3H), 3.10 (s, 3H), 4.60 (br m, 1H), 5.00 (br m, 1H), 6.55 (s, 1H), 6.79(m, 1H), 7.08 (m, 1H), 7.35 (m, 2H), 7.49 (m, 1H), 7.51 (m, 1H), 9.74(s, 1H), 10.95 (t, 1H), 12.40 (s, 1H), 13/15 (s, 1H). MS m/z 564 [M+H]⁺

Example 159N-[2-({[6-(2-Ethyl-5-fluoro-4-hydroxyphenyl)-3-(4-methyl-1H-imidazol-2-yl)-1H-pyrazolo[4,3-c]pyridin-4-yl]amino}methyl)phenyl]-N-methylmethanesulfonamide

The title compound was prepared according to the method described byExample 157 usingN-[2-({[6-(2-ethyl-5-fluoro-4-{[2-(trimethylsilyl)ethoxy]-methoxy}phenyl)-3-iodo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazolo[4,3-c]pyridin-4-yl]amino}methyl)phenyl]-N-methylmethanesulfonamide(Preparation 79) and 2-iodo-5-methyl-1H-imidazole at 115° C. undermicrowave irradiation for 30 minutes. Following deprotection the residuewas purified using preparative HPLC. ¹H NMR (400 MHz, DMSO-d₆): δ ppm0.95 (t, 1.5H), 0.99 (t, 1.5H), 1.99 (s, 1.5H), 2.32 (s, 1.5H), 3.05 (m,3H), 3.10 (m, 3H), 4.66 (br m, 1H), 4.99 (br m, 1H), 6.56 (m, 1H),6.77-6.90 (m, 2H), 7.01-7.09 (m, 1H), 7.27-7.36 (m, 2H), 7.46-7.61 (m,2H), 9.74 (br s, 1H), 10.95 (m, 1H), 12.55 (s, 0.5H), 12.69 (s, 0.5H),13.22 (br s, 1H). MS m/z 550 [M+H]⁺

Example 160 Intermediate2-Fluoro-4-(4-((2-(methylthio)ethyl)amino)-3-(4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl)-5-(2,2,2-trifluoroethyl)phenol

The title compound was prepared according to the method described byExample 157 using6-(5-fluoro-2-(2,2,2-trifluoroethyl)-4-((2-(trimethylsilyl)ethoxy)-methoxy)phenyl)-3-iodo-N-(2-(methylthio)ethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-c]pyridin-4-amine(Preparation 379) and tert-butyl2-iodo-6,7-dihydro-1H-imidazo[4,5-c]pyridine-5(4H)-carboxylate(WO20131014567A1). MS m/z 522 [M+H]⁺

Example 1614-[3-(5-Benzyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yl)-4-{[2-(methylsulfanyl)-ethyl]amino}-1H-pyrazolo[4,3-c]pyridin-6-yl]-2-fluoro-5-(2,2,2-trifluoroethyl)phenol

To a suspension of anhydrous magnesium sulfate (40 mg, 0.33 mmol) and2-fluoro-4-(4-((2-(methylthio)ethyl)amino)-3-(4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl)-5-(2,2,2-trifluoroethyl)phenol(Example 161, 44 mg, 0.08 mmol) in methanol (2.5 mL) was added asolution of benzaldehyde (0.017 mL, 0.17 mmol) in methanol (2.5 mL). Thereaction was stirred for 1 hour at 55° C. before cooling to roomtemperature and adding sodium cyanoborohydride (10.6 mg, 0.17 mmol). Thereaction was stirred at room temperature for 18 hours. The reaction wasfiltered and concentrated in vacuo. The residue was partitioned between20% IPA in DCM and water. The organic layer was collected, dried oversodium sulfate and concentrated in vacuo. The residue was purified bypreparative TLC to afford the title compound (20 mg, 39%). ¹H NMR (400MHz, DMSO-d₆): δ ppm 1.90 (s, 1.5H), 1.98 (s, 1.5H), 2.66-2.88 (m, 6H),3.47 (m, 2H), 3.64-3.72 (m, 4H), 4.03-4.11 (m, 2H), 6.62 (s, 1H), 7.01(m, 1H), 7.27-7.38 (m, 6H), 10.11 (s, 1H), 10.68 (t, 0.5H), 10.75 (t,0.5H), 12.46 (s, 0.5H), 12.58 (s, 0.5H), 13.23 (s, 1H). MS m/z 612[M+H]⁺

Example 162N-[2-({[6-(2-Ethyl-5-fluoro-4-hydroxyphenyl)-3-(1H-pyrazol-1-yl)-1H-pyrazolo[4,3-c]pyridin-4-yl]amino}methyl)phenyl]-N-methylmethanesufonamide

To a solution ofN-[2-({[6-(2-ethyl-5-fluoro-4-{[2-(trimethylsilyl)ethoxy]-methoxy}phenyl)-3-iodo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazolo[4,3-c]pyridin-4-yl]amino}methyl)phenyl]-N-methylmethanesufonamide(Preparation 79, 250 mg, 0.29 mmol) in DMSO (0.5 mL) was added pyrazole(19.88 mg, 0.29 mmol), PEG (500 mg), cesium carbonate (133 mg, 0.41mmol), cuprous oxide (1.25 mg, 0.01 mmol) and4,7-dimethoxy-1,10-phenanthroline (5.61 mg, 0.023 mmol) and the reactionwas heated to 110° C. for 18 hours. The reaction was cooled, dilutedwith EtOAc and washed with water and brine. The organic layer was driedover sodium sulfate and concentrated in vacuo. The residue was purifiedusing silica gel column chromatography eluting with 27% EtOAc inhexanes. The residue (77 mg, 0.097 mmol) was treated with TFA (2.5 mL)and stirred at room temperature for 30 minutes. The reaction wasconcentrated in vacuo, dissolved in MeOH (5 mL) and cooled in ice water.Ethylene diamine was added dropwise until the solution was basic, withstirring for 15 minutes. The solution was concentrated in vacuo andpurified using silica gel column chromatography eluting with 6% MeOH inDCM to afford the title compound (32 mg, 62%).

¹H NMR (400 MHz, DMSO-ds): δ ppm 0.93 (t, 3H), 2.49 (m, 2H), 3.05 (s,3H), 3.07 (s, 3H), 4.67 (br m, 1H), 5.00 (br m, 1H), 6.60 (s, 1H), 6.66(m, 1H), 6.80 (m, 1H), 7.05 (m, 1H), 7.31 (m, 2H), 7.45 (m, 2H), 7.91(s, 1H), 8.54 (s, 1H), 9.61 (t, 1H), 9.76 (s, 1H), 13.11 (s, 1H). MS m/z536 [M+H]⁺

Example 163N-{2-[({6-[5-Fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-3-(1H-pyrazol-1-yl)-1H-pyrazolo[4,3-c]pyridin-4-yl}amino)methyl]phenyl}-N-methylmethanesulfonamide

The title compound was prepared according to the method described forExample 162 usingN-methyl-N-(2-{[(6-[5-fluoro-2-(2,2,2-trifluoroethyl)-4-{[2-(trimethylsilyl)ethoxy]methoxy}phenyl]-3-iodo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazolo[4,3-c]pyridin-4-yl)amino]-methyl}phenyl)methanesulfonamide(Preparation 105) and pyrazole. Following deprotection the residue waspurified using silica gel column chromatography eluting with 45% EtOAcin hexanes. ¹H NMR (400 MHz, DMSO-d₆): δ ppm 3.06 (m, 6H), 3.40 (m, 2H),4.64 (br m, 1H), 4.93 (br m, 1H), 6.66 (m, 2H), 6.94 (m, 1H), 7.19-7.22(m, 1H), 7.28-7.34 (m, 2H), 7.41-7.50 (m, 2H), 7.93 (s, 1H), 8.57 (s,1H), 9.71 (t, 1H), 10.11 (brs, 1H), 13.21 (brs, 1H). MS m/z 590 [M+H]⁺

Example 164N-{2-[({6-[5-Fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-3-(5-methyl-4H-1,2,4-triazol-3-yl)-1H-pyrazolo[4,3-c]pyridin-4-yl}amino)methyl]phenyl}-N-methylmethanesulfonamide

To a solution of acetimidamide hydrochloride (33 mg, 0.35 mmol) in2-methoxyethanol (3 mL) was added DIPEA (0.087 mL, 0.50 mmol) followedbyN-(2-(((6-(5-fluoro-2-(2,2,2-trifluoroethyl)-4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-3-(hydrazinecarbonyl)-1-((2-(tri-methylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-c]pyridin-4-yl)amino)-methyl)phenyl)-N-methyl-methanesulfonamide(Preparation 374, 120 mg, 0.143 mmol). The reaction was stirred at 85°C. for 18 hours. The reaction was quenched with water and extracted withDCM. The organic extracts were collected, dried over sodium sulfate andconcentrated in vacuo. The residue was purified using silica gel columnchromatography eluting with 27% EtOAc in DCM. The residue (100 mg, 0.12mmol) was treated with TFA (2 mL) and stirred at room temperature for 30minutes. The reaction was concentrated in vacuo, dissolved in MeOH (5mL) and cooled in ice water. Ethylene diamine was added dropwise untilthe solution was basic, with stirring for 15 minutes. The solution wasconcentrated in vacuo and purified using preparative TLC to afford thetitle compound (40 mg, 54%). ¹H NMR (400 MHz, DMSO-d₆): δ ppm 1.75 (s,3H), 3.04-3.12 (m, 6H), 3.68 (m, 2H), 4.70 (br m, 1H), 5.00 (br m, 1H),6.67 (m, 1H), 6.97 (m, 1H), 7.20-7.22 (m, 1H), 7.25-7.29 (m, 2H), 7.34(m, 2H), 7.85 (m, 1H), 10.08-10.25 (m, 1H), 13.36 (s, 0.5H), 13.71 (s,0.5H), 14.02 (s, 0.5H), 14.52 (s, 0.5H). MS m/z 605 [M+H]⁺

Example 165N-[2-({[6-(2-Ethyl-5-fluoro-4-hydroxyphenyl)-3-(5-methyl-4H-1,2,4-triazol-3-yl)-1H-pyrazolo[4,3-c]pyridin-4-yl]amino}methyl)phenyl]-N-methylmethanesulfonamide

To a solution of6-[5-fluoro-2-ethyl-4-{[2-(trimethylsilyl)ethoxy]methoxy}phenyl]-4-({2-[methyl(methylsulfonyl)amino]benzyl}amino)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazolo[4,3-c]pyridine-3-carboxylicacid (Preparation 373, 180 mg, 0.23 mmol) in THF (12 mL) was addedhydrazine hydrochloride (39.82 mg, 0.58 mmol), BOP (257 mg, 0.58 mmol)and DIPEA (0.122 mL, 0.70 mmol). The reaction was stirred at roomtemperature for 18 hours. The reaction was quenched with water,extracted into DCM, the organic extracts collected, dried over sodiumsulfate and concentrated in vacuo. The residue was purified by silicagel column chromatography eluting with 8% MeOH in DCM. The residue wasadded to a solution of acetimidamide hydrochloride (30 mg, 0.32 mmol)and DIPEA (0.08 mL, 0.44 mmol) in 2-methoxyethanol (3 mL) and thereaction was heated to 85° C. for 18 hours. The reaction was cooled andquenched by the addition of water and extracted into DCM. The organiclayer was collected, washed with brine, dried over sodium sulfate andconcentrated in vacuo. The residue was purified by preparative TLC. Theresidue was treated with TFA (2 mL) and stirred at room temperature for30 minutes. The reaction was concentrated in vacuo, dissolved in MeOH (5mL) and cooled in ice water. Ethylene diamine was added dropwise untilthe solution was basic, with stirring for 15 minutes. The solution wasconcentrated in vacuo and purified using preparative TLC to afford thetitle compound (30 mg, 88%). ¹H NMR (400 MHz, DMSO-d₆): δ ppm 0.97 (t,3H), 2.20 (s, 3H), 2.56 (m, 2H), 3.04 (s, 3H), 3.12 (s, 3H), 4.65 (br m,1H), 5.00 (br m, 1H), 6.66 (m, 1H), 6.83 (m, 1H), 7.02 (m, 1H), 7.33 (m,2H), 7.51-7.57 (m, 2H), 9.78 (m, 1H), 10.13 (m, 1H), 13.27 (s, 0.5H),13.62 (s, 0.5H), 13.99 (s, 0.5H), 14.49 (s, 0.5H). MS m/z 549 [M−H]⁻

Example 166N-{2-[({6-[5-Fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-3-[5-(6-methylpyridin-3-yl)-4H-1,2,4-triazol-3-yl]-1H-pyrazolo[4,3-c]pyridin-4-yl}amino)methyl]phenyl}-N-methylmethanesulfonamide

To a solution ofN-(2-(((6-(5-fluoro-4-methoxy-2-(2,2,2-trifluoroethyl)phenyl)-3-(hydrazinecarbonyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-c]pyridin-4-yl)amino)methyl)phenyl)-N-methylmethanesulfonamide(Preparation 376, 160 mg, 0.22 mmol) in n-butanol (2 mL) was added5-cyano-2-methyl pyridine (65 mg, 0.55 mmol) and potassium carbonate (16mg, 0.12 mmol). The reaction mixture was heated to 150° C. undermicrowave irradiation for 50 minutes. The reaction was cooled andconcentrated in vacuo. The residue was partitioned between water andethyl acetate. The organic extracts were washed with brine, dried oversodium sulfate and concentrated in vacuo. The residue was purified bysilica gel column chromatography eluting with 15% MeOH in DCM followedby preparative TLC. The residue was treated with boron tribromide (0.047mL 0.47 mmol) and the reaction stirred at room temperature for 30minutes. The reaction was concentrated in vacuo and partitioned betweensaturated aqueous NaHCO₃ and EtOAc. The organic extracts were dried oversodium sulfate, concentrated in vacuo and purified by preparative TLC toafford the title compound (19 mg, 41%). ¹H NMR (400 MHz, DMSO-d₆): δ ppm1.22 (s, 3H), 3.03 (s, 3H), 3.07 (s, 3H), 3.71 (m, 2H), 4.75 (br m, 1H),5.05 (br m, 1H), 6.78 (s, 1H), 6.96 (m, 1H), 7.22-7.38 (m, 4H), 7.40 (m,2H), 7.75 (m, 1H), 8.93 (m, 1H), 10.01 (br m, 1H), 13.80 (br m, 1H). MSm/z 682 [M+H]⁺

Example 1674-(5-{6-[5-Fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-4-({5-hydroxy-2-[methyl(methylsulfonyl)amino]benzyl}amino)-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-4H-1,2,4-triazol-3-yl)piperidine-1-carboxamide

To a solution ofN-(2-(((6-(5-fluoro-4-methoxy-2-(2,2,2-trifluoroethyl)phenyl)-3-(5-(piperidin-4-yl)-4H-1,2,4-triazol-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)methyl)-4-methoxyphenyl)-N-methylmethanesulfonamide(Preparation 371, 70 mg, 0.097 mmol) in DCM (12 mL) was addedtriethylamine (0.02 mL, 0.146 mmol) and trimethylsilylisocyanate (0.013mL, 0.097 mmol). The reaction was quenched with water, and the organicextracts were dried over sodium sulfate and concentrated in vacuo. Theresidue was dissolved in DCM (10 mL) and boron tribromide (0.041 mL,0.41 mmol) was added at 0° C. and stirred for 3 hours. The reaction wasquenched with saturated aqueous sodium bicarbonate solution followed byextraction with 20% IPA in DCM. The organic extracts were collected,dried over sodium sulfate and concentrated in vacuo. The residue waspurified by preparative TLC eluting with 10% MeOH in DCM to afford thetitle compound (34 mg, 78%). ¹H NMR (400 MHz, DMSO-d₆): δ ppm 1.42 (m,2H), 1.75 (m, 2H), 2.67-2.75 (m, 2H), 3.01 (s, 3H), 3.08 (s, 3H), 3.17(m, 1H), 3.89 (m, 2H), 4.34 (m, 2H), 4.69 (m, 1H), 4.99 (m, 1H), 5.93(br s, 2H), 6.76 (m, 1H), 6.86 (m, 1H), 6.99 (m, 1H), 7.36 (m, 1H), 7.75(m, 1H), 9.66 (br s, 1H), 10.38-10.50 (m, 2H), 13.72 (br s, 0.5H), 14.05(br s, 0.5H), 14.20 (br s, 0.5H), 14.72 (br s, 0.5H). MS m/z 734 [M+H]⁺

Example 168N-(2-{[(6-[5-Fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-3-{5-[1-(pyrrolidin-1-ylacetyl)piperidin-4-yl]-4H-1,2,4-triazol-3-yl}-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino]methyl}phenyl)-N-methylmethanesulfonamide

To a solution ofN-(2-(((6-(5-fluoro-4-methoxy-2-(2,2,2-trifluoroethyl)phenyl)-3-(5-(piperidin-4-yl)-4H-1,2,4-triazol-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)methyl)-phenyl)-N-methylmethanesulfonamide(Preparation 372, 90 mg, 0.13 mmol) and 2-(pyrrolidin-1-yl)acetic acid(21 mg, 0.13 mmol) in DCM (10 mL) was added DIPEA (0.065 mL, 0.39 mmol)followed by BOP (58 mg, 0.13 mmol). The reaction was allowed to stir atroom temperature for 18 hours. The reaction was concentrated in vacuoand partitioned between 20% IPA in DCM and water. The organic extractswere washed with brine, dried and concentrated in vacuo. The residue waspurified by silica gel column chromatography eluting with 12% MeOH inDCM. The residue was dissolved in DCM and treated with boron tribromide(0.083 mL, 0.87 mmol) at 0° C. The reaction was stirred at roomtemperature for 18 hours before the addition of another aliquot of borontribromide (0.25 mL) and further stirring for 3 hours. The reaction wasquenched by the addition of saturated aqueous sodium bicarbonatesolution and extracted with 20% IPA in DCM. The organic extract wasseparated, dried over sodium sulfate and concentrated in vacuo. Theresidue was purified by silica gel column chromatography eluting with15% MeOH in DCM to afford the title compound (41 mg, 42%).

¹H NMR (400 MHz, DMSO-d₆): δ ppm 1.33 (m, 1H), 1.48 (m, 1H), 1.71-1.90(m, 6H), 2.59-2.70 (m, 3H), 2.97 (m, 1H), 3.06 (m, 4H), 3.13 (s, 3H),3.31 (m, 2H), 3.90 (m, 1H), 4.08 (m, 1H), 4.19 (m, 1H), 4.31 (m, 2H),4.79 (br m, 1H), 5.12 (br m, 1H), 6.99 (m, 1H), 7.35-7.59 (m, 4H), 7.73(m, 1H), 10.44 (m, 2H), 13.93 (br s, 1H), 14.55 (br s, 1H). MS m/z 786[M+H]⁺

Example 169N-{2-[({6-[5-Fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-3-(4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl}amino)methyl]-4-hydroxyphenyl}-N-methylmethanesulfonamide

The title compound was prepared according to the method described forExample 29 usingN-(2-(((6-(5-fluoro-4-methoxy-2-(2,2,2-trifluoroethyl)phenyl)-3-(4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)methyl)-4-methoxyphenyl)-N-methylmethanesulfonamide(Preparation 370). ¹H NMR (400 MHz, DMSO-d₆): δ ppm 2.32-2.67 (m, 2H),2.91 (m, 2H), 3.02 (s, 3H), 3.10 (s, 3H), 3.32 (m, 2H), 4.34 (m, 2H),4.67 (m, 1H), 5.00 (m, 1H), 6.72 (m, 1H), 6.74 (m, 1H), 6.98 (m, 1H),7.33 (m, 1H), 7.72 (m, 1H), 9.65 (m, 1H), 11.26-11.33 (m, 1H), 12.62 (m,1H), 13.59 (m, 1H). MS m/z 662 [M+H]⁺

Example 170N-{2-[({3-(5-Acetyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yl)-6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-4-yl}amino)methyl]-4-hydroxyphenyl}-N-methylmethanesulfonamide

To a solution ofN-(2-(((6-(5-fluoro-4-methoxy-2-(2,2,2-trifluoroethyl)phenyl)-3-(4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)methyl)-4-methoxyphenyl)-N-methylmethanesulfonamide(Preparation 370, 200 mg, 0.29 mmol) and DIPEA (0.096 ml, 0.58 mmol) inDCM (35 mL) at 0° C. was added acetyl chloride (0.021 mL, 0.29 mmol) andthe reaction stirred at room temperature for 2 hours. The reaction wasconcentrated in vacuo and partitioned between EtOAc and water. Theorganic phase was dried, concentrated in vacuo and purified by silicagel column chromatography eluting with 5% MeOH in DCM. The residue wasdissolved in DCM (10 mL) and treated with boron tribromide (0.083 mL,0.87 mmol) at 0° C. The reaction was stirred at room temperature for 18hours before the addition of another aliquot of boron tribromide (0.25mL) with further stirring for 3 hours. The reaction was quenched by theaddition of saturated aqueous sodium bicarbonate solution and extractedwith 20% IPA in DCM. The organic extract was separated, dried oversodium sulfate and concentrated in vacuo. The residue was purified bypreparative TLC eluting with 10% MeOH in DCM to afford the titlecompound (25 mg, 38%). ¹H NMR (400 MHz, DMSO-d₆): δ ppm (tautomers?)2.50 (m, 3H), 2.62 (m, 2H), 3.02 (s, 3H), 3.15 (s, 3H), 3.70 (m, 3H),4.35 (m, 4H), 4.54 (m, 1H), 5.00 (m, 1H), 6.71-7.00 (m, 3H), 7.35 (m,1H), 7.70 (m, 1H), 9.60 (m, 1H), 10.37 (m, 1H), 11.54-11.67 (m, 1H),13.65 (s, 1H). MS m/z 704 [M+H]⁺

Example 171N-[2-(Dimethylamino)ethyl]-2-{6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-4-({5-hydroxy-2-[methyl(methylsulfonyl)amino]benzyl}amino)-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxamide

To a solution ofN-(2-(((6-(5-fluoro-4-methoxy-2-(2,2,2-trifluoroethyl)phenyl)-3-(4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-amino)methyl)-4-methoxyphenyl)-N-methylmethanesulfonamide(Preparation 370, 80 mg, 0.116 mmol) in DCM (5 mL), was added borontribromide (0.077 mL, 0.81 mmol) at 0° C. and stirred for 2 hours.Another aliquot of boron tribromide (7 eq) was added and the reactionmixture was stirred at room temperature for a further 2 hours. Thereaction was quenched by the addition of saturated aqueous sodiumbicarbonate solution and extracted with 20% IPA in DCM. The organicextract was separated, dried over sodium sulfate and concentrated invacuo. The residue was purified by preparative TLC. The residue wasdissolved in THF (1 mL) and added to a solution of N,N-dimethylamine (6mL) in THF (1.5 mL) and bromoethylisocyanate (0.02 mL, 0.18 mmol) thathad stirred at 0° C. for 10 minutes. The reaction was stirred at roomtemperature for 18 hours. The reaction was concentrated in vacuo andpurified using preparative TLC to afford the title compound (15 mg,21%). 25 minute HPLC QC (Sunfire C18 (150×4.6 mm×5u), mobile phaseA=MeCN, mobile phase B=10 mM ammonium acetate in water Rt=2.59 minutes.MS m/z 776 [M+H]⁺

Example 172 Intermediate Racemic2-Fluoro-4-(4-((3-hydroxy-2-methlpropyl)amino)-3-(4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-5-(2,2,2-trifluoroethyl)phenol

The title compound was prepared according to the method described forExample 157 using tert-butyl2-iodo-6,7-dihydro-1H-imidazo[4,5-c]pyridine-5(4H)-carboxylate(WO20131014567A1) and racemic3-((6-(5-fluoro-2-(2,2,2-trifluoroethyl)-4-((2-(trimethylsilyl)ethoxy)-methoxy)phenyl)-3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)-2-methylpropan-1-ol(Preparation 380). MS m/z 521 [M+H]⁺

Example 1734-(3-(5-Benzyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yl)-4-((3-hydroxy-2-methylpropyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-2-fluoro-5-(2,2,2-trifluoroethyl)phenol

The title compound was prepared according to the method described forExample 161 using racemic2-fluoro-4-(4-((3-hydroxy-2-methylpropyl)amino)-3-(4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-5-(2,2,2-trifluoroethyl)phenol(Example 172). The residue was purified by preparative HPLC. 10 minuteHPLC QC (Gemini NX-C18 (50×4.6 mm×3u), mobile phase A=0.05% formic acidin water, mobile phase B=MeCN Rt=4.20 minutes MS m/z 611 [M+H]⁺

Example 174 Intermediate6-(5-Fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl)-4-((5-hydroxy-2-(N-methylmethylsulfonamido)benzyl)amino)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylicacid

The title compound was prepared according to the method described forPreparation 11 usingN-(2-(((6-(5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)methyl)-4-hydroxyphenyl)-N-methylmethanesulfonamide(Preparation 271). MS m/z 585 [M+H]⁺

Preparation 16-(2-Ethyl-5-fluoro-4-{[2-(trimethylsilyl)ethoxy]methoxy}phenyl)-N-methyl-4-({2-[methyl(sulfamoyl)amino]benzyl}amino)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazolo[4,3-c]pyridine-3-carboxamide

To a solution of6-(2-ethyl-5-fluoro-4-{[2-(trimethylsilyl)ethoxy]methoxy}phenyl)-N-methyl-4-{[2-(methylamino)benzyl]amino}-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazolo[4,3-c]pyridine-3-carboxamide(Preparation 14, 500 mg, 0.705 mmol) in THF (2 mL) was added NaH (28.2mg, 0.70 mmol) at 0° C. followed by dropwise addition of sulfamoylchloride (97 mg, 0.84 mmol). The reaction was allowed to warm to roomtemperature for 1 hour. The reaction was quenched with water andextracted with ethyl acetate. The organic extracts were separated, driedover sodium sulfate and concentrated in vacuo. The residue was purifiedby silica gel column chromatography eluting with 40% EtOAc in Hexanes toafford the title compound as an off-white solid (350 mg, 62%). ¹H NMR(400 MHz, DMSO-d₆): δ ppm −0.11 (s, 9H), −0.02 (s, 9H), 0.80 (t, 2H),0.84-0.91 (m, 5H), 2.59 (m, 2H), 2.83 (s, 3H), 3.01 (s, 3H), 3.57 (t,2H), 3.75 (t, 2H), 4.75 (br s, 1H), 5.00 (br s, 1H), 5.29 (s, 2H), 5.72(s, 2H), 6.96 (s, 1H), 7.04 (s, 1H), 7.13 (m, 1H), 7.22-7.43 (m, 4H),8.85 (m, 1H), 9.68 (m, 1H). MS m/z 788 [M+H]⁺

Preparation 26-[5-Fluoro-2-(2,2,2-trifluoroethyl)-4-{[2-(trimethylsilyl)ethoxy]methoxy}phenyl]-4-{[2-(methyl{[3-(morpholin-4-yl)propyl]sulfonyl]amino)benzyl}amino}-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazolo[4,3-c]pyridine-3-carboxamide

To a solution of4-[(2-{[(3-chloropropyl)sulfonyl](methyl)amino}benzyl)amino]-6-[5-fluoro-2-(2,2,2-trifluoroethyl)-4-{[2-(trimethylsilyl)ethoxy]methoxy}phenyl]-1-{[2-(tri-methylsilyl)ethoxy]-methyl}-1H-pyrazolo[4,3-c]pyridine-3-carboxamide(Preparation 4, 290 mg, 0.32 mmol) in EtOH (2 mL) was added morpholine(0.5 mL) and the reaction was heated to 110° C. under microwaveirradiation for 75 minutes. The reaction was cooled, concentrated invacuo and partitioned between EtOAc and water. The organic layer wascollected, dried over sodium sulfate and concentrated in vacuo. Theresidue was purified using preparative TLC to afford the title compound(70 mg, 80%). MS m/z 940 [M+H]⁺

Preparation 36-(5-Fluoro-2-(2,2,2-trifluoroethyl)-4-((2-trimethylsilyl)ethoxy)methoxy)phenyl)-N-methyl-4-((2-(N-methyl-1H-pyrazole-4-sulfonamido)benzyl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide

To a solution of6-(5-fluoro-2-(2,2,2-trifluoroethyl)-4-fluoro-4-{[2-(trimethyl-silyl)ethoxy]-methoxy}phenyl)-N-methyl-4-{[2-(methylamino)benzyl]amino}-1-{[2-(trimethylsilyl)ethoxy]-methyl}-1H-pyrazolo[4,3-c]pyridine-3-carboxamide(Preparation 17, 150 mg, 0.19 mmol) in THF (10 mL) was added1H-pyrazole-4-suffonylchloride (0.03 mL, 0.19 mmol) at 0° C. Thereaction mixture was allowed to stir at room temperature for 18 hours.The reaction was concentrated in vacuo and purified using silica gelcolumn chromatography to afford the title compound (76 mg, 43%). ¹H NMR(400 MHz, DMSO-d₆): δ ppm −0.11 (s, 9H), −0.03 (s, 9H), 0.79-0.89 (m,4H), 2.86 (d, 3H), 2.99 (s, 3H), 3.57 (t, 2H), 3.76 (m, 4H), 4.80 (br m,1H), 4.97 (br m, 1H), 5.30 (s, 2H), 5.73 (s, 2H), 6.70 (m, 1H), 7.09 (s,1H), 7.18-7.71 (m, 5H), 7.71 (s, 1H), 8.29 (s, 1H), 8.90 (m, 1H), 9.84(m, 1H), 13.75 (s, 1H). MS m/z 893 [M+H]⁺

The following Preparations (Preparations 4-10) were prepared accordingto the method described for Preparation 3 using either6-[5-fluoro-2-(2,2,2-trifluoroethyl)-4-{[2-(trimethylsilyl)-ethoxy]methoxy}phenyl]-4-{[2-(methylamino)benzyl]amino}-1-{[2-(trimethylsilyl)ethoxy]-methyl}-1H-pyrazolo[4,3-c]pyridine-3-carboxamide(Preparation 16) or6-(5-fluoro-2-(2,2,2-trifluoroethyl)-4-fluoro-4-{[2-(trimethylsilyl)ethoxy]methoxy}phenyl)-N-methyl-4-{[2-(methylamino)benzyl]amino}-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazolo[4,3-c]pyridine-3-carboxamide(Preparation 17) and the appropriate sulfonyl chloride as describedbelow:

Preparation Number Name Data 4 4-[(2-{[(3-chloropropyl)sulfonyl]- MS m/z889 [M + H]⁺ (methyl)amino}benzyl)amino]-6- Using3-chloropropanesulfonyl [5-fluoro-2-(2,2,2-trifluoroethyl)-4- chloride.{[2-(trimethylsilyl)ethoxy]meth- oxy}phenyl]-1-{[2-(trimethylsilyl)-ethoxy]methyl}-1H-pyrazolo[4,3- c]pyridine-3-carboxamide 56-[5-fluoro-2-(2,2,2-trifluoroethyl)- MS m/z 975 [M + H]⁺4-{[2-(trimethylsilyl)ethoxy]- ¹H NMR (400 MHz, DMSO-d₆): δmethoxy}phenyl]-4-{[2-(methyl{[6- ppm −0.11 (s, 9H), −0.03 (s, 9H),(morpholin-4-yl)pyridin-3-yl]sulfo- 0.80-0.89 (m, 4H), 2.99 (s, 3H),3.56-3.84 nyl}amino)benzyl]amino}-1-{[2- (m, 14H), 4.78 (m, 1H), 4.93(m, 1H), 5.30 (trimethylsilyl)ethoxy]methyl}-1H- (s, 2H), 5.73 (s, 2H),6.80 (d, 1H), 6.90 pyrazolo[4,3-c]pyridine-3- (d, 1H), 7.10 (s, 1H),7.19-7.33 (m, 3H), carboxamide 7.42 (m, 1H), 7.63 (m, 1H), 7.98 (s, 1H),8.27 (m, 2H), 9.83 (m, 1H). Using 6-morpholin-4-yl-pyridine-3- sulfonylchloride. 6 6-[5-fluoro-2-(2,2,2-trifluoroethyl)- MS m/z 918 [M + H]⁺4-{[2-(trimethylsilyl)ethoxy]- Using 6-methylpyridine-3-sulfonylmethoxy}phenyl]-N-methyl-4-[(2- chloride.{methyl[(6-methylpyridin-3-yl)sulfo- nyl]amino}benzyl)amino]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H- pyrazolo[4,3-c]pyridine-3-carboxamide 7 6-[5-fluoro-2-(2,2,2-trifluoroethyl)- MS m/z 904 [M + H]⁺4-{[2-(trimethylsilyl)ethoxy]- Using 6-methylpyridine-3-sulfonylmethoxy}phenyl]-4-[(2-{methyl[(6- chloride.methylpyridin-3-yl)sulfonyl]amino}- benzyl)amino]-1-{[2-(trimethyl-silyl)ethoxy]methyl}-1H- pyrazolo[4,3-c]pyridine-3- carboxamide 84-((2-(N,1-dimethyl-1H-imidazole-4- MS m/z 907 [M + H]⁺sulfonamido)benzyl)amino)-6-(5- Using 1-methyl-1H-imidazole-4-fluoro-2-(2,2,2-trifluoroethyl)-4- sulfonylchloride.((2-(trimethylsilyl)ethoxy)meth- oxy)phenyl)-N-methyl-1-((2-(trimethylsilyl)-ethoxy)methyl)- 1H-pyrazolo[4,3-c]pyridine-3-carboxamide 9 6-[5-fluoro-2-(2,2,2-trifluoroethyl)- MS m/z 885 [M + H]⁺4-{[2-(trimethylsilyl)ethoxy]- Using 2-methoxyethanesulfonylmethoxy}phenyl]-4-[(2-{[(2- chloride. methoxyethyl)sulfonyl](methyl)ami-no}benzyl)amino]-N-methyl-1- {[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazolo-[4,3-c]pyridine-3- carboxamide 106-[5-fluoro-2-(2,2,2-trifluoroethyl)- Using pyridine-3-sulfonylchloride. 4-{[2-(trimethylsilyl)ethoxy]- Taken directly on to the nextstep. methoxy}phenyl]-4-({2-[methyl- l(pyridin-3-ylsulfonyl)amino]ben-zyl}amino)-1-{[2-(trimethylsilyl)- ethoxy]methyl}-1H-pyrazolo[4,3-c]pyridine-3-carboxamide

Preparation 116-[5-Fluoro-2-(2,2,2-trifluoroethyl)-4-{[2-(trimethylsilyl)ethoxy]methoxy}phenyl]-4-({5-methoxy-2-[methyl(methylsulfonyl)amino]benzyl}amino)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazolo[4,3-c]pyridine-3-carboxylicacid

To a solution ofN-(2-{[(6-[5-fluoro-2-(2,2,2-trifluoroethyl)-4-{[2-(trimethyls-ilyl)ethoxy]-methoxy}phenyl]-3-iodo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazolo[4,3-c]pyridin-4-yl)-amino]methyl}-4-methoxyphenyl)-N-methylmethanesulfonamide(Preparation 85, 250 mg, 0.26 mmol) in MeOH (4 mL) was added molybdenumhexacarbonyl (84.91 mg, 0.32 mmol), DBU (0.119 mL, 0.80 mmol) andPd(OAc)₂ (4 mg, 0.02 mmol). The reaction was heated to 125° C. for 15minutes under microwave irradiation. The reaction was cooled, dilutedwith EtOAc and filtered through celite. The filtrate was concentrated invacuo and purified using silica gel column chromatography eluting with10% MeOH in DCM to afford the title compound (100 mg, 51%). MS m/z 858[M+H]⁺

Preparation 126-[5-Fluoro-2-(2,2,2-trifluoroethyl)-4-{[2-(trimethylsilyl)ethoxy]methoxy}phenyl]-4-({2-[methyl(methylsulfonyl)amino]benzyl}amino)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazolo[4,3-c]pyridine-3-carboxylicacid

The title compound was prepared according to the method described forPreparation 11 usingN-methyl-N-(2-{[(6-[5-fluoro-2-(2,2,2-trifluoroethyl)-4-{[2-(trimethylsilyl)ethoxy]methoxy}phenyl]-3-iodo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazolo[4,3-c]pyridin-4-yl)amino]-methyl}phenyl)methanesulfonamide(Preparation 105). MS m/z 829 [M+H]⁺

Preparation 136-(5-Fluoro-2-(2,2,2-trifluoroethyl)-4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-N-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-4-((2-(1,3,3-trimethylureido)benzyl)amino)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide

To a solution of6-(5-fluoro-2-(2,2,2-trifluoroethyl)-4-fluoro-4-{[2-(trimethylsilyl)ethoxy]-methoxy}phenyl)-N-methyl-4-{[2-(methylamino)benzyl]amino}-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazolo[4,3-c]pyridine-3-carboxamide(Preparation 17, 50 mg, 0.06 mmol) in THF (5 mL) was added sodiumhydride (1.88 mg, 0.08 mmol) at 0° C. After stirring for 2 minutes,dimethylsulfamoyl chloride (15 mg, 0.11 mmol) was added and the reactionwas stirred for 1 hour. The reaction was partitioned between EtOAc andwater, the organic layer was collected, dried over sodium sulfate andconcentrated in vacuo. The residue was dissolved in DMF (1 mL) andtreated with cesium carbonate (64 mg, 0.19 mmol) followed by methyliodide (27 mg, 0.19 mmol). The reaction was stirred at room temperaturefor 18 hours before quenching with ammonium chloride and extraction withEtOAc. The organic layer was collected and purified using preparativeTLC to afford the title compound (45 mg, 78%). MS m/z 870 [M+H]⁺

Preparation 146-(2-Ethyl-5-fluoro-4-{[2-(trimethylsilyl)ethoxy]methoxy}phenyl)-N-methyl-4-{[2-(methyl-amino)benzyl}amino]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazolo[4,3-c]pyridine-3-carboxamide

To a solution of benzyl[2-({[6-(2-ethyl-5-fluoro-4-{[2-(trimethylsilyl)-ethoxy]methoxy}phenyl)-3-(methylcarbamoyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazolo[4,3-c]pyridin-4-yl]amino}-methyl)phenyl]methylcarbamate(Preparation 18, 775 mg, 0.91 mmol) in EtOH (25 mL) was added 10% Pd/C(100 mg) and the reaction was hydrogenated at room temperature at 30 psifor 1 hour. The reaction was filtered, the filtrate was concentrated invacuo and the residue was purified by silica gel column chromatographyeluting with 15% EtOAc in hexanes to afford the title compound (530 mg,81%). ¹H NMR (400 MHz, DMSO-d₆): δ ppm −0.11 (s, 9H), −0.01 (s, 9H),0.81 (t, 2H), 0.88 (t, 2H), 1.00 (t, 2H), 2.38 (s, 3H), 2.69 (m, 2H),2.82 (s, 3H), 3.56 (t, 2H), 3.77 (t, 2H), 4.59 (m, 2H), 5.33 (s, 2H),5.71 (s, 2H), 6.02 (m, 1H), 6.44 (m, 1H), 6.55 (m, 1H), 6.98 (s, 1H),7.04-7.19 (m, 2H), 7.22 (m, 1H), 8.84 (m, 1H), 9.69 (m, 1H). MS m/z 709[M+H]⁺

Preparation 156-[5-Fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-4-[({2-[methyl(methylsulfonyl)amino]-pyridin-3-yl}methyl)amino]-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide

The title compound was prepared according to the method described forPreparation 14 using6-[4-(benzyloxy)-5-fluoro-2-(2,2,2-trifluoroethyl)phenyl]-4-[({2-[methyl(methylsulfonyl)amino]pyridin-3-yl}methyl)amino]-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide(Preparation 22). The residue was purified by silica gel columnchromatography eluting with 25% EtOAc in DCM. ¹H NMR (400 MHz, DMSO-d₆):δ ppm 1.58 (m, 2H), 1.74 (m, 1H), 1.93-2.10 (m, 3H), 3.10 (s, 1H), 3.12(s, 3H), 3.61 (m, 1H), 3.74 (m, 2H), 3.90 (m, 1H), 4.82 (m, 2H), 5.88(m, 1H), 6.95 (d, 1H), 7.03 (s, 1H), 7.25 (d, 1H), 7.36 (m, 1H), 7.81(m, 1H), 7.97 (br s, 1H), 8.19 (br s, 1H), 8.41 (m, 1H), 9.82 (t, 1H),10.15 (s, 1H). MS m/z 652 [M+H]⁺

Preparation 166-[5-Fluoro-2-(2,2,2-trifluoroethyl)-4-{[2-(trimethylsilyl)ethoxy]methoxy})phenyl]-4-{[2-(methyl-amino)benzyl]amino}-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazolo[4,3-c]pyridine-3-carboxamide

The title compound was prepared according to the method described forPreparation 14 using benzyl(2-{[(3-carbamoyl-6-[5-fluoro-2-(2,2,2-trifluoroethyl)-4-{[2-(trimethylsilyl)-ethoxy]methoxy}phenyl]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazolo[4,3-c]pyridin-4-yl)-amino]methyl}phenyl)methylcarbamate(Preparation 23). The residue was purified by silica gel columnchromatography eluting with 30% EtOAc in hexanes. MS m/z 749 [M+H]⁺

Preparation 176-(5-Fluoro-2-(2,2,2-trifluoroethyl)-4-fluoro-4-{[2-(trimethylsilyl)ethoxy]methoxy}phenyl)-N-methyl-4-{[2-(methylamino)benzyl]amino}-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazolo[4,3-c]pyridine-3-carboxamide

The title compound was prepared according to the method described forPreparation 14 using benzyl[2-({[6-(5-fluoro-2-(2,2,2-trifluoroethyl)-4-{[2-(trimethylsilyl)ethoxy]methoxy}-phenyl)-3-(methylcarbamoyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazolo[4,3-c]pyridin-4-yl]amino}methyl)phenyl]methylcarbamate(Preparation 19). ¹H NMR (400 MHz, DMSO-d₆): δ ppm −0.11 (s, 9H), −0.01(s, 9H), 0.81 (t, 2H), 0.89 (t, 2H), 2.50 (s, 3H), 2.84 (d, 3H), 3.58(t, 2H), 3.76 (t, 2H), 3.95 (q, 2H), 4.58 (d, 2H), 5.33 (s, 2H), 5.73(s, 2H), 5.74 (br s, 1H), 6.45-6.54 (m, 2H), 7.05-7.11 (m, 3H),7.35-7.39 (m, 2H), 8.87 (m, 1H), 9.73 (m, 1H). MS m/z 763 [M+H]⁺

Preparation 18 Benzyl[2-({[6-(2-ethyl-5-fluoro-4-[2-(trimethylsilyl)ethoxy]methoxy}phenyl-3-(methylcarbamoyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazolo[4,3-c]pyridin-4-yl]amino}methyl)phenyl]methylcarbamate

To a solution of benzyl[2-({[6-(2-ethyl-5-fluoro-4-{[2-(trimethylsilyl)ethoxy]methoxy}phenyl)-3-iodo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazolo[4,3-c]pyridin-4-yl]amino}methyl)phenyl]methylcarbamate(Preparation 91, 1 g, 1 mmol) in methylamine/THF (10 mL) was added DBU(0.49 mL, 3.23 mmol), Pd(OAc)₂ (17 mg, 0.08 mmol) followed by molybdenumhexacarbonyl (0.29 mg, 1.09 mmol). The reaction was heated to 100° C.under microwave irradiation for 10 minutes. The reaction was cooled,concentrated in vacuo and diluted with EtOAc. The mixture was filteredthrough celite, the filtrate concentrated in vacuo and purified usingsilica gel column chromatography eluting with 47% EtOAc in hexanes toafford the title compound (775 mg, 84%). ¹H NMR (400 MHz, DMSO-d₆): δppm −0.10 (s, 9H), −0.01 (s, 9H), 0.79 (t, 2H), 0.90 (m, 5H), 2.57 (m,2H), 2.83 (d, 3H), 3.08 (s, 1H), 3.59 (t, 2H), 3.74 (t, 2H), 4.53 (m,1H), 4.71 (m, 1H), 4.88 (m, 1H), 5.00 (m, 1H), 5.27 (s, 1H), 5.75 (s,2H), 6.98 (s, 1H), 7.08-7.42 (m, 11H), 8.83 (m, 1H), 9.67 (m, 1H). MSm/z 843 [M+H]⁺

Preparation 19 Benzyl[2-({[6-(5-fluoro-2-(2,2,2-trifluoroethyl)-4-[2-(trimethylsilyl)ethoxy]methoxy}phenyl)-3-(methylcarbamoyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazolo[4,3-c]pyridin-4-yl]amino}methyl)phenyl]methylcarbamate

A solution of6-[5-fluoro-2-(2,2,2-trifluoroethyl)-4-{[2-(trimethylsilyl)-ethoxy]methoxy}phenyl]-N-methyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazolo[4,3-c]pyridine-3-carboxamide-5-oxide(Preparation 117, 3.2 g, 4.96 mmol) in DMF (100 mL) was treated withbenzylmethyl[2-({[(4-nitrophenoxy)carbonyl]amino}-methyl)phenyl]carbamate(Preparation 178, 2.68 g, 6.16 mmol) and triethylamine (0.68 mL, 4.96mmol) and heated at 80° C. for 16 hours. Further benzylmethyl[2-({[(4-nitrophenoxy)carbonyl]amino}methyl)phenyl]carbamate (1.24eq) and triethylamine (1 eq) were added and the reaction allowed tocontinue for 6 hours. The reaction was cooled, concentrated in vacuo andpurified using silica gel column chromatography to afford the titlecompound as an oil (4.2 g, 94%). MS m/z 897 [M+H]⁺

Preparation 206-(2-Ethyl-5-fluoro-4-{[2-(trimethylsilyl)ethoxy]methoxy}phenyl)-4-((2-[methyl(methylsulfonyl)amino]benzyl}amino)-N-(6-methylpyridin-3-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazolo[4,3-c]pyridine-3-carboxamide

The title compound was prepared according to the method described forPreparation 18 usingN-[2-({[6-(2-ethyl-5-fluoro-4-{[2-(trimethylsilyl)ethoxy]-methoxy}phenyl)-3-iodo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazolo[4,3-c]pyridin-4-yl]amino}methyl)phenyl]-N-methylmethanesulfonamide(Preparation 79) and 6-methylpyridin-3-amine with DBU at 100° C. for 10minutes under microwave irradiation. The reaction was cooled,concentrated in vacuo and purified using silica gel columnchromatography eluting with 7% heptanes in EtOAc. MS m/z 864 [M+H]⁺

Preparation 216-[5-Fluoro-2-(2,2,2-trifluoroethyl)-4-{[2-(trimethylsilyl)ethoxy]methoxy}phenyl]-4-({4-methoxy-2-[methyl(methylsulfonyl)amino]benzyl}amino)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazolo[4,3-c]pyridine-3-carboxamide

To a solution ofN-(2-{[(6-[5-fluoro-2-(2,2,2-trifluoroethyl)-4-{[2-(trimethylsilyl)-ethoxy]-methoxy}phenyl]-3-iodo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazolo[4,3-c]pyridin-4-yl)-amino]methyl}-5-methoxyphenyl)-N-methylmethanesulfonamide(Preparation 89, 350 mg, 0.37 mmol) in MeOH (2 mL) was added DBU (0.16mL, 1.19 mmol), palladium acetate (5.86 mg, 0.03 mmol) and molybdenumhexacarbonyl (99 mg, 0.37 mmol) and the reaction was heated to 100° C.for 10 minutes under microwave irradiation. The reaction was cooled,concentrated in vacuo and purified directly using silica gel columnchromatography eluting with 12% MeOH in DCM. The resulting residue wasdissolved in anhydrous THF (5 mL) and NMM (0.033 mL, 0.30 mmol) wasadded followed by isobutylchloroformate (0.04 mL, 0.30 mmol) at −20° C.The reaction was stirred for 2 hours at this temperature before theaddition of aqueous ammonia (0.5 mL) with further stirring for 1 hour.The reaction was partitioned between EtOAc and water, the organic layercollected, washed with brine, dried over sodium sulfate and concentratedin vacuo. The residue was purified using silica gel columnchromatography eluting with 42% EtOAc in hexanes to afford the titlecompound (102 mg, 32% over 2 steps). MS m/z 857 [M+H]⁺

The following Preparations (Preparations 22-26) were prepared accordingto the method described for Preparation 21 using the appropriate iodointermediate as described below:

Preparation Number Name Data 22 6-[4-(benzyloxy)-5-fluoro-2- MS m/z 742[M + H]⁺ (2,2,2-trifluoroethyl)phenyl]- UsingN-{3-[({6-[4-(benzyloxy)-5-fluoro-2- 4-[({2-(2,2,2-trifluoroethyl)phenyl]-3-iodo-1-[methyl(methylsulfonyl)amino]pyridin- (tetrahydro-2H-pyran-2-yl)-1H-3-yl}methyl)amino]- pyrazolo[4,3-c]pyridin-4-1-(tetrahydro-2H-pyran-2-yl)- yl}amino)methyl]pyridin-2-yl}-N-1H-pyrazolo[4,3-c]pyridine-3- methylmethanesulfonamide (Preparationcarboxamide 93). 23 Benzyl (2-{[(3-carbamoyl-6- MS m/z 883 [M + H]⁺[5-fluoro-2-(2,2,2- Using benzyl (2-{[(6-[5-fluoro-2-(2,2,2-trifluoroethyl)-4-{[2- trifluoroethyl)-4-{[2-(trimethylsilyl)ethoxy]-(trimethylsilyl)ethoxy]methoxy}phenyl]- methoxy}phenyl]-3-iodo-1-{[2-1-{[2- (trimethylsilyl)-ethoxy]methyl}-1H-(trimethylsilyl)ethoxy]methyl}- pyrazolo[4,3-c]pyridin-4-1H-pyrazolo[4,3-c]pyridin-4- yl)amino]methyl}phenyl)methylcarbamateyl)amino]methyl}phenyl)methylcarbamate (Preparation 92). 246-[5-fluoro-4-methoxy-2- MS m/z 803 [M + H]⁺(2,2,2-trifluoroethyl)phenyl]- Using N-(2-{[(6-[5-fluoro-2-(2,2,2-4-({5-methoxy-2- trifluoroethyl)-4-{[2-(trimethylsilyl)ethoxy]-[methyl(phenylsulfonyl)- methoxy}pheny.l]-3-iodo-1-{[2-amino]benzyl}amino)-1-{[2- (trimethylsilyl)-ethoxy]methyl}-1H-(trimethylsilyl)ethoxy]methyl}-pyrazolo[4,3-c]pyridin-4-yl)amino]methyl}- 1H-pyrazolo[4,3-c]pyridine-3-5-methoxyphenyl)-N- carboxamide methylmethanesulfonamide (Preparation108). 25 N-ethyl-N-(2-{[(6-[5-fluoro-2- MS m/z 933 [M + H]⁺(2,2,2-trifluoroethyl)-4-{[2- UsingN-ethyl-N-(2-{[(6-[5-fluoro-2-(2,2,2-(trimethylsilyl)ethoxy]methoxy}phenyl]- trifluoroethyl)-4-{[2-3-iodo-1-{[2- (trimethylsilyl)ethoxy]methoxy}phenyl]-3-(trimethylsilyl)- iodo-1-{[2-(trimethylsilyl)ethoxy]methyl}-ethoxy]methyl}-1H- 1H-pyrazolo[4,3-c]pyridin-4-pyrazolo[4,3-c]pyridin-4- yl)amino]methyl}-4- yl)amino]methyl}-4-methoxyphenyl)benzenesulfonamide methoxyphenyl)benzenesulfonamide(Preparation 90). 26 6-(2-cyclopropyl-5-fluoro-4- MS m/z 669 [M + H]⁺methoxyphenyl)-4-({2- Using N-[2-({[6-(2-cyclopropyl-5-fluoro-4-[methyl(methylsulfonyl)amino]benzyl}amino)- methoxyphenyl)-3-iodo-1-{[2-1-{[2- (trimethylsilyl)-ethoxy]methyl}-1H- (trimethylsilyl)-pyrazolo[4,3-c]pyridin-4- ethoxy]methyl}-1H- yl]amino}methyl)phenyl]-N-pyrazolo[4,3-c]pyridine-3- methylmethanesulfonamide (Preparationcarboxamide 109).

Preparation 276-(4-(Benzyloxy)-5-fluoro-2-(2,2,2-trifluoroethyl)phenyl)-N-(tert-butyl)-4-((2-(N-methylmethylsulfonamido)benzyl)amino)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide

To a solution ofN-(2-(((6-(4-(benzyloxy)-5-fluoro-2-(2,2,2-trifluoroethyl)phenyl)-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridin-4-yl)amino)methyl)phenyl)-N-methyl-methanesulfonamide(Preparation 60, 5.8 g, 7.04 mmol) in THF (15 mL) was added molybdenumhexacarbonyl (1.872 g, 7.04 mmol), DBU (3.15 mL) and Pd(OAc)₂ (111 mg,0.15 mmol), and t-butyl amine (6 mL). The reaction was heated in asealed tube to 100° C. for 45 minutes. The reaction was cooled, filteredand concentrated in vacuo. The residue was purified using silica gelcolumn chromatography eluting with 29% EtOAc in hexanes to afford thetitle compound (4 g, 71%). ¹H NMR (400 MHz, DMSO-d₆): 5 ppm 1.45 (s,9H), 1.67-1.73 (m, 2H), 1.91-2.02 (m, 2H), 2.44 (m, 2H), 3.05 (s, 3H),3.10 (s, 3H), 3.66-3.95 (m, 4H), 4.78-4.86 (m, 2H), 5.21 (s, 2H), 5.86(m, 1H), 7.04 (s, 1H), 7.27-7.50 (m, 11H), 7.73 (s, 1H), 9.66 (t, 1H).MS m/z 797 [M+H]⁺

The following Preparations (Preparations 28-38) were prepared accordingto the method described for Preparation 27 using the appropriate iodointermediate as described below:

Preparation Number Name Data 28 6-(4-benzyloxy)-5-fluoro-2- MS m/z 811[M + H]⁺ (2,2,2-trifluoroethyl)phenyl- UsingN-(2-(((6-(4-(benzyloxy)-5-fluoro-2- N-(tert-butyl)-4-((5-methyl-2-(2,2,2-trifluoroethyl)phenyl)-3-iodo-1- (N-(tetrahydro-2H-pyran-2-yl)-1H- methylmethylsulfonamido)benzyl)amino)-pyrazolo[4,3-c]pyridine-4- 1-(tetrahydro-yl)amino)methyl)-4-methylphenyl)-N- 2H-pyran-2-yl)-1H-methylmethanesulfonamide (Preparation pyrazolo[4,3-c]pyridine-3- 94).carboxamide 29 6-(4-(benzyloxy)-5-fluoro-2- MS m/z 826 [M + H]⁺(2,2,2-trifluoroethyl)phenyl)- UsingN-(2-(((6-(4-(benzyloxy)-5-fluoro-2- N-(tert-butyl)-4-((5-methoxy-(2,2,2-trifluoroethyl)phenyl)-3-iodo-1- 2-(N-(tetrahydro-2H-pyran-2-yl)-1H- methylmethylsulfonamido)benzyl)amino)-pyrazolo[4,3-c]pyridin-4-yl)amino)methyl)- 1-(tetrahydro-4-methoxyphenyl)-N- 2H-pyran-2-yl)-1H- methylmethanesulfonamide(Preparation pyrazolo[4,3-c]pyridine-3- 103). carboxamide 306-(4-(benzyloxy)-5-fluoro-2- MS m/z 831 [M + H]⁺(2,2,2-trifluoroethyl)phenyl)- UsingN-(2-(((6-(4-(benzyloxy)-5-fluoro-2- N-(tert-butyl)-4-((5-chloro-2-(2,2,2-trifluoroethyl)phenyl)-3-iodo-1- (N-(tetrahydro-2H-pyran-2-yl)-1H- methylmethylsulfonamido)benzyl)amino)-pyrazolo[4,3-c]pyridin-4-yl)amino)methyl)- 1-(tetrahydro-4-chlorophenyl)-N- 2H-pyran-2-yl)-1H- methylmethanesulfonamide(Preparation pyrazolo[4,3-c]pyridine-3- 101). carboxamide 316-(4-(benzyloxy)-5-fluoro-2- MS m/z 825 [M + H]⁺(2,2,2-trifluoroethyl)phenyl)- UsingN-(2-(((6-(4-(benzyloxy)-5-fluoro-2- N-(tert-butyl)-4-((2-(N-(2,2,2-trifluoroethyl)phenyl)-3-iodo-1- ethylmethylsulfonamido)-5-(tetrahydro-2H-pyran-2-yl)-1H- methylbenzyl)amino)-1-pyrazolo[4,3-c]pyridin-4-yl)amino)methyl)- (tetrahydro-2H-pyran-2-yl)-4-methylphenyl)-N- 1H-pyrazolo[4,3-c]pyridine-3- ethylmethanesulfonamide(Preparation carboxamide 104). 32 6-(4-benzyloxy)-5-fluoro-2- MS m/z 825[M + H]⁺ (2,2,2-trifluoroethyl)phenyl- UsingN-(2-(((6-(4-(benzyloxy)-5-fluoro-2- N-(tert-butyl)-4-((2-(N-(2,2,2-trifluoroethyl)phenyl)-3-iodo-1-ethylethylsulfonamido)benzyl)amino)- (tetrahydro-2H-pyran-2-yl)-1H-1-(tetrahydro-2H- pyrazolo[4,3-c]pyridine-4-pyran-2-yl)-1H-pyrazolo[4,3- yl)amino)methyl)phenyl)-N-c]pyridine-3-carboxamide ethylethanesulfonamide (Preparation 95). 336-(4-(benzyloxy)-5-fluoro-2- MS m/z 826 [M + H]⁺(2,2,2-trifluoroethyl)phenyl)- UsingN-(3-(((6-(4-(benzyloxy)-5-fluoro-2- N-(tert-butyl)-4-(((2-(N-(2,2,2-trifluoroethyl)phenyl)-3-iodo-1- ethylmethylsulfonamido)-5-(tetrahydro-2H-pyran-2-yl)-1H- methylpyridin-3-pyrazolo[4,3-c]pyridin-4-yl)amino)methyl)- yl)methyl)amino)-1-5-methylpyridin-2-yl)-N- (tetrahydro-2H-pyran-2-yl)-ethylmethanesulfonamide (Preparation 1H-pyrazolo[4,3-c]pyridine-3- 100).carboxamide 34 6-(4-(benzyloxy)-5-fluoro-2- MS m/z 829 [M + H]⁺(2,2,2-trifluoroethyl)phenyl)- UsingN-(2-(((6-(4-(benzyloxy)-5-fluoro-2- N-(tert-butyl)-4-((2-(N-(2,2,2-trifluoroethyl)phenyl)-3-iodo-1- ethylmethylsulfonamido)-5-(tetrahydro-2H-pyran-2-yl)-1H- fluorobenzyl)amino)-1-pyrazolo[4,3-c]pyridin-4-yl)amino)methyl)- (tetrahydro-2H-pyran-2-yl)-4-fluorophenyl)-N- 1H-pyrazolo[4,3-c]pyridine-3- ethylmethanesulfonamide(Preparation carboxamide 96). 35 6-(4-(benzyloxy)-5-fluoro-2- MS m/z 845[M + H]⁺ (2,2,2-trifluoroethyl)phenyl)- UsingN-(2-(((6-(4-(benzyloxy)-5-fluoro-2- N-(tert-butyl)-4-((2-(N-(2,2,2-trifluoroethyl)phenyl)-3-iodo-1- ethylmethylsulfonamido)-5-(tetrahydro-2H-pyran-2-yl)-1H- chlorobenzyl)amino)-1-pyrazolo[4,3-c]pyridin-4-yl)amino)methyl)- (tetrahydro-2H-pyran-2-yl)-4-chlorophenyl)-N- 1H-pyrazolo[4,3-c]pyridine-3- ethylmethanesulfonamide(Preparation carboxamide 97). 36 6-(4-(benzyloxy)-5-fluoro-2- MS m/z 811[M + H]⁺ (2,2,2-trifluoroethyl)phenyl)- UsingN-(2-(((6-(4-(benzyloxy)-5-fluoro-2- N-(tert-butyl)-4-((2-(N-(2,2,2-trifluoroethyl)phenyl)-3-iodo-1-ethylmethylsulfonamido)benzyl)amino)- (tetrahydro-2H-pyran-2-yl)-1H-1-(tetrahydro-2H- pyrazolo[4,3-c]pyridin-4- pyran-2-yl)-1H-pyrazolo[4,3-yl)amino)methyl)phenyl)-N- c]pyridine-3-carboxamideethylmethanesulfonamide (Preparation 102). 376-(4-(benzyloxy)-5-fluoro-2- MS m/z 811 [M + H]⁺(2,2,2-trifluoroethyl)phenyl)- UsingN-(2-(((6-(4-(benzyloxy)-5-fluoro-2- N-(tert-butyl)-4-((2-(N-(2,2,2-trifluoroethyl)phenyl)-3-iodo-1-methylethylsulfonamido)benzyl)amino)- (tetrahydro-2H-pyran-2-yl)-1H-1-(tetrahydro-2H- pyrazolo[4,3-c]pyridin-4- pyran-2-yl)-1H-pyrazolo[4,3-yl)amino)methyl)phenyl)-N- c]pyridine-3-carboxamidemethylethanesulfonamide (Preparation 98). 386-(4-(benzyloxy)-5-fluoro-2- MS m/z 812 [M + H]⁺(2,2,2-trifluoroethyl)phenyl)- UsingN-(3-(((6-(4-(benzyloxy)-5-fluoro-2- N-(tert-butyl)-4-(((5-methyl-2-(2,2,2-trifluoroethyl)phenyl)-3-iodo-1- (N-(tetrahydro-2H-pyran-2-yl)-1H- methylmethylsulfonamido)pyridin-pyrazolo[4,3-c]pyridin-4-yl)amino)methyl)- 3-yl)methyl)amino)-1-5-methylpyridin-2-yl)-N- (tetrahydro-2H-pyran-2-yl)-methylmethanesulfonamide (Preparation 1H-pyrazolo[4,3-c]pyridine-3- 99).carboxamide

Preparation 396-[5-Fluoro-4-methoxy-2-(2,2,2-trifluoroethyl)phenyl]-N-methyl-4-[({3-[methyl(phenylsulfonyl)amino]pyrazin-2-yl}methyl)amino]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazolo[4,3-c]pyridine-3-carboxamide

To a solution of4-chloro-6-[5-fluoro-4-methoxy-2-(2,2,2-trifluoroethyl)phenyl]-N-methyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazolo[4,3-c]pyridine-3-carboxamide(Preparation 118, 150 mg, 0.27 mmol) in n-Butanol (4 mL) was addedN-[3-(aminomethyl)pyrazin-2-yl]-N-methylbenzenesulfonamide (Preparation219, 114 mg, 0.41 mmol) and DIPEA (0.17 mL 0.96 mmol). The reaction washeated to 90° C. in a sealed tube for 18 hours. The reaction wasquenched by the addition of water and extracted with EtOAc. The organiclayer was collected, dried over sodium sulfate and concentrated invacuo. The residue was purified by silica gel column chromatographyeluting with 30-50% EtOAc in hexanes to afford the title compound as ayellow solid (110 mg, 51%). MS m/z 789 [M+H]⁺

The following Preparations (Preparations 40-59) were prepared accordingto the method described for Preparation 39 using the appropriatechloropyridine and the appropriate amine as described below:

Preparation Number Name Data 40 4-[({3-[ethyl(methyl- MS m/z 741 [M +H]⁺ sulfonyl)amino]pyrazin-2- Using 4-chloro-6-[5-fluoro-4-methoxy-2-yl}methyl)amino]-6-[5-fluoro- (2,2,2-trifluoroethyl)phenyl]-N-methyl-1-4-methoxy-2-(2,2,2- {[2-(trimethylsilyl)ethoxy]methyl}-1H-trifluoroethyl)phenyl]-N- pyrazolo[4,3-c]pyridine-3-carboxamidemethyl-1-{[2- (Preparation 118) and N-[3-(trimethylsilyl)ethoxy]methyl}- (aminomethyl)pyrazin-2-yl]-N-1H-pyrazolo[4,3-c]pyridine-3- ethylmethanesulfonamide (Preparationcarboxamide 221). 41 N-ethyl-4-[({3- MS m/z 755 [M + H]⁺[ethyl(methylsulfonyl)amino]pyrazin- Using4-chloro-6-[5-fluoro-4-methoxy-2- 2-yl}methyl)amino]-6-(2,2,2-trifluoroethyl)phenyl]-N-ethyl-1-{[2-[5-fluoro-4-methoxy-2-(2,2,2- (trimethylsilyl)ethoxy]methyl}-1H-trifluoroethyl)phenyl]-1-{[2- pyrazolo[4,3-c]pyridine-3-carboxamide(trimethylsilyl)ethoxy]methyl}- (Preparation 119)1H-pyrazolo[4,3-c]pyridine-3- and N-[3-(aminomethyl)pyrazin-2-yl]-N-carboxamide ethylmethanesulfonamide (Preparation 221). 426-[5-fluoro-4-methoxy-2- MS m/z 726 [M + H]⁺(2,2,2-trifluoroethyl)phenyl]- Using 4-chloro-6-[5-fluoro-4-methoxy-2-N-methyl-4-[({4- (2,2,2-trifluoroethyl)phenyl]-N-methyl-1-[methyl(methyl- {[2-(trimethylsilyl)ethoxy]methyl}-1H-sulfonyl)amino]pyridin-3- pyrazolo[4,3-c]pyridine-3-carboxamideyl}methyl)amino]-1-{[2- (Preparation 118) and N-[3-(trimethylsilyl)ethoxy]methyl}- (aminomethyl)pyridin-4-1H-pyrazolo[4,3-c]pyridine-3- yl]methanesulfonamide (Preparationcarboxamide 197). 43 6-[5-fluoro-2-(2,2,2- MS m/z 842 [M + H]⁺trifluoroethyl)-4-{[2- Using 4-chloro-6-[5-fluoro-2-(2,2,2-(trimethylsilyl)- trifluoroethyl)-4-{[2- ethoxy]methoxy}phenyl]-N-(trimethylsilyl)ethoxy]methoxy}phenyl]-N- methyl-4-[({3-[methyl(methyl-methyl-1-{[2- sulfonyl)amino]pyridin-2-(trimethylsilyl)ethoxy]methyl}-1H- yl}methyl)amino]-1-{[2-pyrazolo[4,3-c]pyridine-3-carboxamide (trimethylsilyl)ethoxy]methyl}-(Preparation 122) and N-(2- 1H-pyrazolo[4,(aminomethyl)pyridine-3-yl)-N- 3-c]pyridine-3- methylmethanesulphonamide carboxamide (WO2008/129380A1). 44 6-[5-fluoro-2-(2,2,2- MSm/z 856 [M + H]⁺ trifluoroethyl)-4-{[2- Using4-chloro-6-[5-fluoro-2-(2,2,2- (trimethylsilyl)- trifluoroethyl)-4-{[2-ethoxy]methoxy}phenyl]-N- (trimethylsilyl)ethoxy]methoxy}phenyl]-N-methyl-4-[({5-methyl-2- methyl-1-{[2-[methyl(methylsulfonyl)amino]pyridin- (trimethylsilyl)ethoxy]methyl}-1H-3-yl}methyl)amino]- pyrazolo[4,3-c]pyridine-3-carboxamide 1-{[2-(Preparation 122) and N-[3- (trimethylsilyl)ethoxy]methyl}-(aminomethyl)-5-methylpyridin-2-yl]-N- 1H-pyrazolo[4,3-c]pyridine-3-methylmethanesulfonamide (Preparation carboxamide 198). 456-[5-fluoro-2-(2,2,2- MS m/z 904 [M + H]⁺ trifluoroethyl)-4-{[2- Using4-chloro-6-[5-fluoro-2-(2,2,2- (trimethylsilyl)- trifluoroethyl)-4-{[2-ethoxy]methoxy}phenyl]-N- (trimethylsilyl)ethoxy]methoxy}phenyl]-N-methyl-4-({2-[methyl(pyridin- methyl-1-{[2- 3-(trimethylsilyl)ethoxy]methyl}-1H- ylsulfonyl)amino]benzyl}amino)-pyrazolo[4,3-c]pyridine-3-carboxamide 1-{[2- (Preparation 122) and N-[2-(trimethylsilyl)ethoxy]methyl}- (aminomethyl)phenyl]-N-methylpyridine-1H-pyrazolo[4,3-c]pyridine- 3-sulfonamide hydrochloride 3-carboxamide(Preparation 220). 46 6-[5-fluoro-2-(2,2,2- MS m/z 871 [M + H]⁺trifluoroethyl)-4-{[2- Using 4-chloro-6-[5-fluoro-2-(2,2,2-(trimethylsilyl)- trifluoroethyl)-4-{[2- ethoxy]methoxy}phenyl]-4-(trimethylsilyl)ethoxy]methoxy}phenyl]-N- ({5-methoxy-2- methyl-1-{[2-[methyl(methylsulfonyl)amino]benzyl}amino)-(trimethylsilyl)ethoxy]methyl}-1H- N-methyl-1-pyrazolo[4,3-c]pyridine-3-carboxamide {[2- (Preparation 122) and N-[2-(trimethylsilyl)ethoxy]methyl}- (aminomethyl)-4-methoxyphenyl]-N-1H-pyrazolo[4, (methylsulfonyl)methanesulfonamide3-c]pyridine-3-carboxamide hydrochloride (Preparation 191). 476-[5-fluoro-4-methoxy-2- MS m/z 727 [M + H]⁺(2,2,2-trifluoroethyl)phenyl]- Using 4-chloro-6-[5-fluoro-4-methoxy-2-N-methyl-4-[({3- (2,2,2-trifluoroethyl)phenyl]-N-methyl-1-[methyl(methylsulfonyl)amino]pyrazin-{[2-(trimethylsilyl)ethoxy]methyl}-1H- 2-yl}methyl)amino]-pyrazolo[4,3-c]pyridine-3-carboxamide 1-{[2- (Preparation 118) and N-(3-(trimethylsilyl)ethoxy]methyl}- (aminomethyl)pyrazin-2-yl)-N-1H-pyrazolo[4,3-c]pyridine-3- methylmethanesulfonamide carboxamide(WO2008/129380A1). 48 4-[({2-[ethyl(methyl- MS m/z 856 [M + H]⁺sulfonyl)amino]pyridin-3- Using 4-chloro-6-[5-fluoro-2-(2,2,2-yl}methyl)amino]-6-[5-fluoro- trifluoroethyl)-4-{[2-2-(2,2,2-trifluoroethyl)-4-{[2-(trimethylsilyl)ethoxy]methoxy}phenyl]-N-(trimethylsilyl)ethoxy]methoxy}phenyl]- methyl-1-{[2- N-methyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H- (trimethylsilyl)ethoxy]methyl}-pyrazolo[4,3-c]pyridine-3-carboxamide 1H-pyrazolo[4,3-c]pyridine-3-(Preparation 122) and N-[3- carboxamide (aminomethyl)pyridin-2-yl]-N-ethylmethanesulfonamide (Preparation 218). 49 6-[5-fluoro-2-(2,2,2- MSm/z 826 [M + H]⁺ trifluoroethyl)-4-{[2- Using4-chloro-6-[5-fluoro-2-(2,2,2- (trimethylsilyl)- trifluoroethyl)-4-{[2-ethoxy]methoxy}phenyl]-N- (trimethylsilyl)ethoxy]methoxy}phenyl]-N-methyl-4-{[2- methyl-1-{[2- (sulfamoylmethyl)-(trimethylsilyl)ethoxy]methyl}-1H- benzyl]amino}-1-{[2-pyrazolo[4,3-c]pyridine-3-carboxamide (trimethylsilyl)ethoxy]methyl}-(Preparation 122) and 1-[2- 1H-pyrazolo[4,3-c]pyridine-3-(aminomethyl)phenyl]methanesulfonamide carboxamide hydrochloride(Preparation 199). 50 N-tert-butyl-4-[({5-chloro-2- MS m/z 932 [M + H]⁺[ethyl(methylsulfonyl)amino]pyridin- UsingN-tert-butyl-4-chloro-6-[5-fluoro-2- 3-yl}methyl)amino]-6-(2,2,2-trifluoroethyl)-4-{[2- [5-fluoro-2-(2,2,2-(trimethylsilyl)ethoxy]methoxy}phenyl]-1- trifluoroethyl)-4-{[2-{[2-(trimethylsilyl)ethoxy]methyl}-1H-(trimethylsilyl)ethoxy]methoxy}phenyl]-pyrazolo[4,3-c]pyridine-3-carboxamide 1-{[2-(trimethyl- (Preparation120) and N-[3- silyl)ethoxy]methyl}-1H-(aminomethyl)-5-chloropyridin-2-yl]-N- pyrazolo[4,3-c]pyridine-3-ethylmethanesulfonamide hydrochloride carboxamide (Preparation 201). 51N-tert-butyl-4-[({5-chloro-2- MS m/z 918 [M + H]⁺[methyl(methylsulfonyl)amino]pyridin- UsingN-tert-butyl-4-chloro-6-[5-fluoro-2- 3-yl}methyl)amino]-(2,2,2-trifluoroethyl)-4-{[2- 6-[5-fluoro-2-(2,2,2-(trimethylsilyl)ethoxy]methoxy}phenyl]-1- trifluoroethyl)-4-{[2-{[2-(trimethylsilyl)ethoxy]methyl}-1H-(trimethylsilyl)ethoxy]methoxy}phenyl]-pyrazolo[4,3-c]pyridine-3-carboxamide 1-{[2- (Preparation 120) and N-[3-(trimethylsilyl)ethoxy]methyl}- (aminomethyl)-5-chloropyridin-2-yl]-N-1H-pyrazolo[4,3- methylmethanesulfonamide hydrochloridec]pyridine-3-carboxamide (Preparation 202). 52N-(2,4-dimethoxybenzyl)-4- MS m/z 876 [M + H]⁺ [({2- Using4-chloro-N-(2,4-dimethoxybenzyl)- [ethyl(methylsulfonyl)amino]pyridin-6-[5-fluoro-4-methoxy-2-(2,2,2- 3-yl}methyl)amino]-6-trifluoroethyl)phenyl]-1-{[2- [5-fluoro-4-methoxy-2-(2,2,2-(trimethylsilyl)ethoxy]methyl}-1H- trifluoroethyl)phenyl]-1-{[2-pyrazolo[4,3-c]pyridine-3-carboxamide (trimethylsilyl)ethoxy]methyl}-(Preparation 121) and N-[3- 1H-pyrazolo[4,3-c]pyridine-(aminomethyl)pyridin-2-yl]-N- 3-carboxamide ethylmethane-sulfonamide(Preparation 218). 53 6-[5-fluoro-4-methoxy-2- MS m/z 726 [M + H]⁺(2,2,2-trifluoroethyl)phenyl]- Using 4-chloro-6-[5-fluoro-4-methoxy-2-N-methyl-4-[({2- (2,2,2-trifluoroethyl)phenyl]-N-methyl-1-[methyl(methylsulfonyl)amino]pyridin-{[2-(trimethylsilyl)ethoxy]methyl}-1H- 3-yl}methyl)-pyrazolo[4,3-c]pyridine-3-carboxamide amino]-1-{[2- (Preparation 118)and N-[3- (trimethylsilyl)ethoxy]methyl}- (aminomethyl)pyridin-2-yl]-N-1H-pyrazolo[4,3- methylmethanesulfonamide (Preparationc]pyridine-3-carboxamide 217). 54 6-[5-fluoro-4-methoxy-2- MS m/z 818[M + H]⁺ (2,2,2-trifluoroethyl)phenyl]- Using4-chloro-6-[5-fluoro-4-methoxy-2- 4-({5-methoxy-2-(2,2,2-trifluoroethyl)phenyl]-N-methyl-1- [methyl(pyridin-3-{[2-(trimethylsilyl)ethoxy]methyl}-1H- ylsulfonyl)amino]benzyl}amino)-pyrazolo[4,3-c]pyridine-3-carboxamide N-methyl-1-{[2- (Preparation 118)and N-[2- (trimethylsilyl)ethoxy]methyl}-(aminomethyl)-4-methoxyphenyl]-N- 1H-pyrazolo[4,3-c]pyridine-3-methylpyridine-3-sulfonamide carboxamide (Preparation 212). 556-((4-benzyloxy)-5-fluoro-2- MS m/z 816 [M + H]⁺(2,2,2-trifluoroethyl)phenyl)- Using 6-(4-(benzyloxy)-5-fluoro-2-(2,2,2-N-(tert-butyl)-4-(((5-fluoro-2- trifluoroethyl)phenyl)-N-(tert-butyl)-4-(N- chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-methylmethylsulfonamido)pyridin- pyrazolo[4,3-c]pyridine-3-carboxamide3-yl)methyl)amino)-1- (Preparation 123) and N-[3-(tetrahydro-2H-pyran-2-yl)- (aminomethyl)-5-fluoropyridin-2-yl]-N-1H-pyrazolo[4,3-c]pyridine-3- methylmethanesulfonamide hydrochloridecarboxamide (Preparation 203). 56 6-((4-benzyloxy)-5-fluoro-2- MS m/z830 [M + H]⁺ (2,2,2-trifluoroethyl)phenyl)- Using6-(4-(benzyloxy)-5-fluoro-2-(2,2,2- N-(tert-butyl)-4-(((5-fluoro-2-trifluoroethyl)phenyl)-N-(tert-butyl)-4- (N-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H- ethylmethylsulfonamido)pyridin-pyrazolo[4,3-c]pyridine-3-carboxamide 3-yl)methyl)amino)-1- (Preparation123) and N-[3- (tetrahydro-2H-pyran-2-yl)-(aminomethyl)-5-fluoropyridin-2-yl]-N- 1H-pyrazolo[4,3-c]pyridine-3-ethylmethanesulfonamide hydrochloride carboxamide (Preparation 204). 576-((4-benzyloxy)-5-fluoro-2- MS m/z 813 [M + H]⁺(2,2,2-trifluoroethyl)phenyl)- Using 6-(4-(benzyloxy)-5-fluoro-2-(2,2,2-N-(tert-butyl)-4-(((3-(N- trifluoroethyl)phenyl)-N-(tert-butyl)-4-ethylmethylsulfonamido)pyrazin- chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-2-yl)methyl)amino)-1- pyrazolo[4,3-c]pyridine-3-carboxamide(tetrahydro-2H-pyran-2-yl)- (Preparation 123) and N-[3-1H-pyrazolo[4,3-c]pyridine-3- (aminomethyl)pyrazin-2-yl]-N- carboxamideethylmethanesulfonamide (Preparation 221). 58 6-(5-fluoro-2-(2,2,2- MSm/z 813 [M + H]⁺ trifluoroethyl)-4-((2- Using4-chloro-6-[5-fluoro-2-(2,2,2- (trimethylsilyl)ethoxy)methoxy)phenyl)-trifluoroethyl)-4-{[2- N-methyl-4-((2-(N-(trimethylsilyl)ethoxy]methoxy}phenyl]-N- methyl-2-oxooxazolidine-3-methyl-1-{[2- sulfonamido)benzyl)amino)-(trimethylsilyl)ethoxy]methyl}-1H- 1-((2-pyrazolo[4,3-c]pyridine-3-carboxamide (trimethylsilyl)ethoxy)methyl)-(Preparation 122) and tert-butyl 2-(N- 1H-pyrazolo[4,3-c]pyridine-methyl-2-oxooxazolidine-3- 3-carboxamide sulfonamido)benzyl-carbamatehydrochloride (Preparation 208). 59 6-(4-(benzyloxy)-5-fluoro-2- MS m/z814 [M + H]⁺ (2,2,2-trifluoroethyl)phenyl)- Using6-(4-(benzyloxy)-5-fluoro-2-(2,2,2- N-(tert-butyl)-4-((5-fluoro-2-trifluoroethyl)phenyl)-N-(tert-butyl)-4- (N-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-methylmethylsulfonamido)benzyl)amino)-pyrazolo[4,3-c]pyridine-3-carboxamide 1-(tetrahydro- (Preparation 123)and N-[2- 2H-pyran-2-yl)-1H- (aminomethyl)-4-fluorophenyl]-N-pyrazolo[4,3-c]pyridine-3- methylmethanesulfonamide hydrochloridecarboxamide (Preparation 186).

Preparation 60N-(2-(((6-(4-(Benzyloxy)-5-fluoro-2-(2,2,2-trifluoroethyl)phenyl)-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridin-4-yl)amino)methyl)phenyl)-N-methylmethanesulfonamide

To a solution of6-[4-(benzyloxy)-5-fluoro-2-(2,2,2-trifluoroethyl)phenyl]-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine5-oxide (Preparation 112, 110 mg, 0.18 mmol) in DMF (5 mL) was added4-nitrophenyl {2-[methyl(methylsulfonyl)amino]benzyl}carbamate(Preparation 166, 82 mg, 0.22 mmol) followed by triethylamine (0.06 mL,0.438 mmol). The reaction was heated to 100° C. for 16 hours. Further4-nitrophenyl {2-[methyl(methylsulfonyl)amino]benzyl}carbamate (1.2 eq)and triethylamine (2.5 eq) were added and the reaction continued at 100°C. for 18 hours. The reaction was cooled, concentrated in vacuo andpartitioned between ice-water and EtOAc. The organic layer wascollected, washed with saturated aqueous potassium carbonate solution,brine, dried over sodium sulfate and concentrated in vacuo. The residuewas purified using silica gel column chromatography eluting with 49%EtOAc in hexanes to afford the title compound (120 mg, 83%). ¹H NMR (400MHz, DMSO-d₆): δ ppm 1.50-1.75 (m, 3H), 1.89 (m, 2H), 2.32 (m, 1H), 3.05(s, 3H), 3.06 (s, 3H), 3.53 (m, 1H), 3.70-3.73 (m, 2H), 3.87 (m, 1H),4.74 (m, 1H), 4.92 (m, 1H), 5.21 (s, 2H), 5.78 (m, 1H), 6.82 (t, 1H),7.11 (s, 1H), 7.27-7.50 (m, 11H). MS m/z 824 [M+H]⁺

Preparation 61N-(4-Chloro-2-{[(6-[5-fluoro-2-(2,2,2-trifluoroethyl)-4-{[2-(trimethylsilyl)ethoxy]methoxy)}phenyl]-3-iodo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazolo[4,3-c]pyridin-4-yl)amino]methyl}phenyl)-N-methylmethanesulfonamide

A solution of6-[5-fluoro-2-(2,2,2-trifluoroethyl)-4-{[2-(trimethylsilyl)ethoxy]-methoxy}phenyl]-3-iodo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazolo[4,3-c]pyridine5-oxide (Preparation 114, 650 mg, 0.91 mmol) in DMF was treated with4-nitrophenyl {5-chloro-2-[methyl(methylsulfonyl)amino]benzyl}carbamate(Preparation 156, 564.76 mg, 1.36 mmol) and triethylamine (0.31 mL, 2.27mmol) and the reaction was heated to 90° C. for 16 hours. Further4-nitrophenyl {5-chloro-2-[methyl(methylsulfonyl)amino]benzyl}carbamate(1.5 eq) and TEA (1.5 eq) were added and the reaction was heated to 90°C. for a further 4 hours. The reaction was cooled and concentrated invacuo. The residue was purified by silica gel column chromatographyeluting with 30% EtOAc in hexanes to afford the title compound (365 mg,42%). MS m/z 944 [M³⁵Cl+H]⁺

The following Preparations (Preparations 62-105) were prepared accordingto the method described for Preparation 61 using6-[5-fluoro-2-(2,2,2-trifluoroethyl)-4-{[2-(trimethylsilyl)ethoxy]methoxy}phenyl]-3-iodo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazolo[4,3-c]pyridine5-oxide (Preparation 114) or6-[5-fluoro-4-methoxy-2-(2,2,2-trifluoroethyl)phenyl]-3-iodo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazolo[4,3-c]pyridine5-oxide (Preparation 113) or6-[4-(benzyloxy)-5-fluoro-2-(2,2,2-trifluoroethyl)phenyl]-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine5-oxide (Preparation 112) and the appropriate aminocarbamate.

Preparation Number Name Data 62 N-ethyl-N-(2-{[(6-[5-fluoro-2- MS m/z938 [M + H]⁺ (2,2,2-trifluoroethyl)-4-{[2- Using 4-nitrophenyl {2-(trimethylsilyl)- [ethyl(ethylsulfonyl)amino]benzyl}carbamateethoxy]methoxy}phenyl]-3-iodo- (Preparation 157). 1-{[2-(trimethylsilyl)ethoxy]methyl}-1H- pyrazolo[4,3-c]pyridin-4- yl)amino]-methyl}phenyl)ethanesulfonamide 63 N-ethyl-N-[2-({[6-(2-ethyl-5- MS m/z884 [M + H]⁺ fluoro-4-{[2- Using 4-nitrophenyl {2-(trimethylsilyl)ethoxy]methoxy}phenyl)-[ethyl(ethylsulfonyl)amino]benzyl}carbamate 3-iodo-1-{[2- (Preparation157). (trimethylsilyl)ethoxy]methyl}-1H- pyrazolo[4,3-c]pyridin-4-yl]amino}methyl)phenyl]ethanesulfon- amide 64N-[2-({[6-(2-ethyl-5-fluoro-4-{[2- MS m/z 870 [M + H]⁺(trimethylsilyl)ethoxy]methoxy}phenyl)- Using 4-nitrophenyl {2- 3-[(ethylsulfonyl)(methyl)amino]benzyl}carbamate iodo-1-{[2- (Preparation159). (trimethylsilyl)ethoxy]methyl}-1H- pyrazolo[4,3-c]pyridin-4-yl]amino}methyl)phenyl]-N- methylethanesulfonamide 654-(2-{[6-(2-ethyl-5-fluoro-4-{[2- MS m/z 779 [M + H]⁺(trimethylsilyl)ethoxy]methoxy}phenyl)- Using 4-nitrophenyl [2-(4- 3-hydroxyphenyl)ethyl]carbamate iodo-1-{[2- (Preparation 158).(trimethylsilyl)ethoxy]methyl}-1H- pyrazolo[4,3-c]pyridin-4-yl]amino}-ethyl)phenol 66 6-(2-ethyl-5-fluoro-4-{[2- MS m/z 715 [M + H]⁺(trimethylsilyl)ethoxy]methoxy}phenyl)- Using 4-nitrophenyl (2-3-iodo-N-(2-methylpropyl)- methylpropyl)carbamate 1-{[2- (Preparation160). (trimethylsilyl)ethoxy]methyl}-1H- pyrazolo[4,3-c]pyridin-4-amine67 N-[4-chloro-2-({[6-(2-ethyl-5- MS m/z 890 [M + H]⁺ fluoro-4-{[2-Using 4-nitrophenyl {5-chloro-2- (trimethylsilyl)ethoxy]methoxy}phenyl)-[methyl(methylsulfonyl)amino]benzyl}carbamate 3-iodo-1-{[2- (Preparation156). (trimethylsilyl)ethoxy]methyl}-1H- pyrazolo[4,3-c]pyridin-4-yl]amino}-methyl)phenyl]-N- methylmethane sulfonamide 68N-[2-({[6-(2-ethyl-5-fluoro-4-{[2- MS m/z 874 [M + H]⁺(trimethylsilyl)ethoxy]methoxy}phenyl)- Using 4-nitrophenyl {5-fluoro-2-3-iodo-1-{[2- [methyl(methylsulfonyl)amino]benzyl}carbamate(trimethylsilyl)ethoxy]methyl}-1H- (Preparation 161).pyrazolo[4,3-c]pyridin-4- yl]amino}-methyl)-4-fluorophenyl]-N-methyl-methane sulfonamide 69N-[2-({[6-(2-ethyl-5-fluoro-4-{[2- MS m/z 874 [M + H]⁺(trimethylsilyl)ethoxy]methoxy}phenyl)- Using 4-nitrophenyl {2-fluoro-6-3-iodo-1-{[2- [methyl(methylsulfonyl)amino]benzyl}carbamate(trimethylsilyl)ethoxy]methyl}-1H- (Preparation 162).pyrazolo[4,3-c]pyridin-4- yl]amino}methyl)-3-fluorophenyl]-N-methylmethane sulfonamide 70 N-ethyl-N-[2-({[6-(2-ethyl-5- MS m/z 870[M + H]⁺ fluoro-4-{[2- Using (trimethylsilyl)ethoxy]methoxy}phenyl)-4-nitrophenyl {2- 3-iodo-1-{[2-[ethyl(methylsulfonyl)amino]benzyl}carbamate(trimethylsilyl)ethoxy]methyl}-1H- (Preparation 163).pyrazolo[4,3-c]pyridin-4- yl]amino}methyl)phenyl]methane sulfon-amide 71N-(cyclopentylmethyl)-6-(2-ethyl- MS m/z 743 [M¹²⁹I + H]⁺5-fluoro-4-{[2- Using 4-nitrobenzyl (trimethylsilyl)ethoxy]-(cyclopentylmethyl)carbamate methoxy}phenyl)-3-iodo-1-{[2- (Preparation164). (trimethylsilyl)ethoxy]methyl}-1H- pyrazolo[4,3-c]pyridin-4-amine72 6-(5-fluoro-2-(2,2,2-trifluoroethyl)- MS m/z 924 [M + H]⁺ 4-((2-Using 4-nitrophenyl {5-methyl-2- (trimethylsilyl)ethoxy)methoxy)phenyl)-[methyl(methylsulfonyl)amino]benzyl}carbamateN-methyl-4-((5-methyl-2-(N- (Preparation 165).methylmethylsulfonamido)benzyl) amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H- pyrazolo[4,3-c]pyridine-3-carboxamide 73 N-ethyl-N-(2-{[(6-[5-fluoro-2- MS m/z 924 [M + H]⁺(2,2,2-trifluoroethyl)-4-{[2- Using 4-nitrophenyl {2-(trimethylsilyl)ethoxy]- [ethyl(methylsulfonyl)amino]benzyl}carbamatemethoxy}phenyl]-3-iodo-1-{[2- (Preparation 163).(trimethylsilyl)ethoxy]methyl}-1H- pyrazolo[4,3-c]pyridin-4-yl)amino]-methyl}phenyl)methane sulfonamide 74N-(2-{[(6-[5-fluoro-2-(2,2,2- MS m/z 924 [M + H]⁺ trifluoroethyl)-4-{[2-Using 4-nitrophenyl {2- (trimethylsilyl)ethoxy]methoxy}-[(ethylsulfonyl)(methyl)amino]benzyl} phenyl]-3-iodo-1-{[2- carbamate(Preparation 159). (trimethylsilyl)-ethoxy]methyl}-1H-pyrazolo[4,3-c]pyridin-4- yl)amino]-methyl}phenyl)-N- methylethanesulfonamide 75 N-(4-fluoro-2-{[(6-[5-fluoro-2- MS m/z 928 [M + H]⁺(2,2,2-trifluoroethyl)-4-{[2- Using 4-nitrophenyl {5-fluoro-2-(trimethylsilyl)- [methyl(methylsulfonyl)amino]benzyl}carbamateethoxy]methoxy}phenyl]-3-iodo- (Preparation 161). 1-{[2-(tri-methylsilyl)ethoxy]methyl}-1H- pyrazolo-[4,3-c]pyridin-4-yl)amino]methyl}phenyl)-N- methylmethanesulfonamide 76N-(3-fluoro-2-{[(6-[5-fluoro-2- MS m/z 928 [M + H]⁺(2,2,2-trifluoroethyl)-4-{[2- Using 4-nitrophenyl {2-fluoro-6-(trimethylsilyl)- [methyl(methylsulfonyl)amino]benzyl}carbamateethoxy]methoxy}phenyl]-3-iodo- (Preparation 162). 1-{[2-(trimethylsilyl)ethoxy]methyl}-1H- pyrazolo[4,3-c]pyridin-4-yl)amino]-methyl}-phenyl)-N- methylmethanesulfonamide 77N-(cyclopentylmethyl)-6-[5-fluoro- MS m/z 795 [M + H]⁺2-(2,2,2-trifluoroethyl)-4-{[2- Using 4-nitrobenzyl (trimethyl-(cyclopentylmethyl)carbamate silyl)ethoxy]methoxy}phenyl]-3-(Preparation 164). iodo-1-{[2- (trimethylsilyl)ethoxy]methyl}-1H-pyrazolo[4,3-c]pyridin-4-amine 78 6-[5-fluoro-2-(2,2,2-trifluoroethyl)-MS m/z 771 [M¹²⁹I + H]⁺ 4-{[2- Using 4-nitrophenyl (2-(trimethylsilyl)ethoxy]methoxy}phenyl]- methylpropyl)carbamate3-iodo-N-(2-methylpropyl)- (Preparation 160). 1-{[2-(trimethylsilyl)ethoxy]methyl}-1H- pyrazolo[4,3-c]pyridin-4-amine 79N-[2-({[6-(2-ethyl-5-fluoro-4-{[2- MS m/z 856 [M + H]⁺(trimethylsilyl)ethoxy]methoxy}phenyl)- Using 4-nitrophenyl {2- 3-[methyl(methylsulfonyl)amino]benzyl}carbamate iodo-1-{[2- (Preparation166). (trimethylsilyl)ethoxy]methyl}-1H- pyrazolo[4,3-c]pyridin-4-yl]amino}-methyl)phenyl]-N- methylmethanesulfonamide 80N-[2-({[6-(2-ethyl-5-fluoro-4-{[2- MS m/z 870 [M + H]⁺(trimethylsilyl)ethoxy]methoxy}phenyl)- Using 4-nitrophenyl {5-methyl-2-3-iodo-1-{[2- [methyl(methylsulfonyl)amino]benzyl}carbamate(trimethylsilyl)ethoxy]methyl}-1H- (Preparation 165).pyrazolo[4,3-c]pyridin-4- yl]amino}-methyl)-4- methylphenyl]-N-methyl-methanesulfonamide 81 N-[2-({[6-(2-ethyl-5-fluoro-4-{[2- MS m/z 918 [M +H]⁺ (trimethylsilyl)ethoxy]methoxy}phenyl)- Using 4-nitrophenyl {2- 3-[methyl(phenylsulfonyl)amino]benzyl}carbamate iodo-1-{[2- (Preparation167). (trimethylsilyl)ethoxy]methyl}-1H- pyrazolo[4,3-c]pyridin-4-yl]amino}-methyl)phenyl]-N- methylbenzene sulfonamide 82N-[4-(2-{[6-(2-ethyl-5-fluoro-4-{[2- MS m/z 918 [M + H]⁺(trimethylsilyl)ethoxy]methoxy}phenyl)- 4-nitrophenyl (2-{4-3-iodo-1-{[2- [(phenylsulfonyl)amino]phenyl}ethyl)(trimethylsilyl)ethoxy]methyl}-1H- carbamate (Preparation 168)pyrazolo[4,3-c]pyridin-4- yl]amino}- ethyl)phenyl]benzenesulfonamide 83N-[2-({[6-(2-ethyl-5-fluoro-4-{[2- MS m/z 886 [M + H]⁺(trimethylsilyl)ethoxy]methoxy}phenyl)- 4-nitrophenyl {2- 3-iodo-1-{[2-[bis(methylsulfonyl)amino]-5- (trimethylsilyl)ethoxy]methyl}-1H-methoxybenzyl}carbamate pyrazolo[4,3-c]pyridin-4- (Preparation 169).yl]amino}-methyl)-4- methoxyphenyl]-N- methylmethanesulfon amide 84Racemic N-[2-(1-{[6-(2-ethyl-5- MS m/z 870 [M + H]⁺ fluoro-4-{[2-Racemic 4-nitrophenyl (1-{2- (trimethylsilyl)ethoxy]-methoxy}phenyl)-[methyl(methylsulfonyl)amino]phenyl}ethyl)carbamate 3-iodo-1-{[2-(Preparation 170). (trimethyl-silyl)ethoxy]methyl}-1H-pyrazolo[4,3-c]pyridin-4- yl]amino}ethyl)phenyl]-N-methylmethanesulfonamide 85 N-(2-{[(6-[5-fluoro-2-(2,2,2- MS m/z 940[M + H]⁺ trifluoroethyl)-4-{[2- 4-nitrophenyl {2-(trimethylsilyl)ethoxy]-methoxy}- [bis(methylsulfonyl)amino]-5-phenyl]-3-iodo-1-{[2- methoxybenzyl}carbamate(trimethylsilyl)ethoxy]methyl}- (Preparation 169).1H-pyrazolo[4,3-c]pyridin-4- yl)amino]methyl}-4- methoxyphenyl)-N-methylmethane-sulfonamide 86 N-(2-{[(6-[5-fluoro-2-(2,2,2- MS m/z 972[M + H]⁺ trifluoroethyl)-4-{[2- Using 4-nitrophenyl {2-(trimethylsilyl)ethoxy]-methoxy}-[methyl(phenylsulfonyl)amino]benzyl}carbamate phenyl]-3-iodo-1-{[2-(Preparation 167). (trimethylsilyl)-ethoxy]methyl}-1H-pyrazolo[4,3-c]pyridin-4- yl)amino]methyl}phenyl)-N-methylbenzenesulfonamide 87 N-(2-{[(6-[5-fluoro-2-(2,2,2- MS m/z 1024[M + H]⁺ trifluoroethyl)-4-{[2-(trimethyl- Using 4-nitrobenzyl (2-silyl)ethoxy]methoxy}-phenyl]-3- {(methylsulfonyl)[2-(tetrahydro-2H-iodo-1-{[2-(trimethylsilyl)- pyran-2- ethoxy]methyl}-1H-pyrazolo[4,3-yloxy)ethyl]amino}benzyl)carbamate c]pyridin-4- (Preparation 171).yl)amino]methyl}phenyl)-N-[2- (tetra-hydro-2H-pyran-2-yloxy)ethyl]methane-sulfonamide 88 N-[2-({[6-(2-ethyl-5-fluoro-4-{[2- MSm/z 886 [M + H]⁺ (trimethylsilyl)ethoxy]methoxy}phenyl)- Using4-nitrophenyl {4-methoxy-2- 3-iodo-1-{[2-[methyl(methylsulfonyl)amino]benzyl}carbamate(trimethylsilyl)ethoxy]methyl}-1H- (Preparation 172).pyrazolo[4,3-c]pyridin-4- yl]amino}methyl)-5- methoxyphenyl]-N-methylmethanesulfon amide 89 N-(2-{[(6-[5-fluoro-2-(2,2,2- MS m/z 940[M + H]⁺ trifluoroethyl)-4-{[2- Using 4-nitrophenyl {4-methoxy-2-(trimethylsilyl)ethoxy]- [methyl(methylsulfonyl)amino]benzyl}carbamatemethoxy}phenyl]-3-iodo-1-{[2- (Preparation 172).(trimethyl-silyl)ethoxy]methyl}- 1H-pyrazolo[4,3-c]pyridin-4-yl)amino]methyl}-5-methoxy- phenyl)-N- methylmethanesulfonamide 90N-ethyl-N-(2-{[(6-[5-fluoro-2- MS m/z 1016 [M + H]⁺(2,2,2-trifluoroethyl)-4-{[2- Using 4-nitrophenyl {2- (trimethylsilyl)-[ethyl(phenylsulfonyl)amino]-5- ethoxy]methoxy}phenyl]-3-iodo-methoxybenzyl}carbamate 1-{[2- (Preparation 176).(trimethylsilyl)ethoxy]methyl}-1H- pyrazolo[4,3-c]pyridin-4-yl)amino]-methyl}-4- methoxyphenyl)benzenesulfonamide 91 benzyl[2-({[6-(2-ethyl-5-fluoro-4- MS m/z 912 [M + H]⁺ {[2- Using benzylmethyl[2-({[(4- (trimethylsilyl)ethoxy]methoxy}phenyl)-nitrophenoxy)carbonyl]amino}methyl)phenyl]carbamate 3-iodo-1-{[2-(Preparation (trimethylsilyl)ethoxy]methyl}-1H- 178).pyrazolo[4,3-c]pyridin-4- yl]amino}- methyl)phenyl]methylcarbamate 92benzyl (2-{[(6-[5-fluoro-2-(2,2,2- MS m/z 966 [M + H]⁺trifluoroethyl)-4-{[2- Using benzyl methyl[2-({[(4-(trimethylsilyl)ethoxy]methoxy}phenyl]-nitrophenoxy)carbonyl]amino}methyl)phenyl]carbamate 3-iodo-1-{[2-(Preparation (trimethylsilyl)ethoxy]methyl}-1H- 178).pyrazolo[4,3-c]pyridin-4- yl)amino]-methyl}- phenyl)methylcarbamate 93N-{3-[({6-[4-(benzyloxy)-5-fluoro- MS m/z 825 [M + H]⁺2-(2,2,2-trifluoroethyl)phenyl]-3- Using 4-nitrophenyl ({2-iodo-1-(tetrahydro-2H-pyran-2- [methyl(methylsulfonyl)amino]pyridin-yl)-1H-pyrazolo-[4,3-c]pyridin-4- 3-yl}methyl)carbamateyl}amino)-methyl]pyridin-2-yl}-N- (Preparation 177).methylmethanesulfonamide 94 N-(2-(((6-(4-(benzyloxy)-5-fluoro- MS m/z838 [M + H]⁺ 2-(2,2,2-trifluoroethyl)phenyl)-3- Using 4-nitrophenyl{5-methyl-2- iodo-1-(tetrahydro-2H-pyran-2-[methyl(methylsulfonyl)amino]benzyl}carbamateyl)-1H-pyrazolo[4,3-c]pyridine-4- (Preparation 165). yl)amino)methyl)-4-methylphenyl)-N-methylmethane- sulfonamide 95N-(2-(((6-(4-(benzyloxy)-5-fluoro- MS m/z 852 [M + H]⁺2-(2,2,2-trifluoroethyl)phenyl)-3- Using 4-nitrophenyl {2-iodo-1-(tetrahydro-2H-pyran-2-[ethyl(ethylsulfonyl)amino]benzyl}carbamateyl)-1H-pyrazolo-[4,3-c]pyridine-4- (Preparation 157).yl)amino)methyl)-phenyl)-N- ethylethanesulfonamide 96N-(2-(((6-(4-(benzyloxy)-5-fluoro- MS m/z 856 [M + H]⁺2-(2,2,2-trifluoroethyl)phenyl)-3- Using 4-nitrophenyl {2-iodo-1-(tetrahydro-2H-pyran-2- [ethyl(methylsulfonyl)amino]-5-yl)-1H-pyrazolo[4,3-c]pyridin-4- fluorobenzyl}carbamateyl)amino)methyl)-4-fluorophenyl)- (Preparation 179).N-ethylmethanesulfonamide 97 N-(2-(((6-(4-(benzyloxy)-5-chloro- MS m/z871 [M + H]⁺ 2-(2,2,2-trifluoroethyl)phenyl)-3- Using 4-nitrophenyl {2-iodo-1-(tetrahydro-2H-pyran-2- [ethyl(methylsulfonyl)amino]-5-yl)-1H-pyrazolo[4,3-c]pyridin-4- chlorobenzyl}carbamateyl)amino)methyl)-4-fluorophenyl)- (Preparation 180).N-ethylmethanesulfonamide 98 N-(2-(((6-(4-(benzyloxy)-5-fluoro- MS m/z838 [M + H]⁺ 2-(2,2,2-trifluoroethyl)phenyl)-3- Using 4-nitrophenyl {2-iodo-1-(tetrahydro-2H-pyran-2- [(ethylsulfonyl)(methyl)amino]benzyl}yl)-1H-pyrazolo[4,3-c]pyridin-4- carbamate (Preparation 159).yl)amino)methyl)-phenyl)-N- methylethanesulfonamide 99N-(3-(((6-(4-(benzyloxy)-5-fluoro- MS m/z 839 [M + H]+2-(2,2,2-trifluoroethyl)phenyl)-3- Using 4-nitrobenzyl ((5-methyl-2-(N-iodo-1-(tetrahydro-2H-pyran-2- methylmethylsulfonamido)pyridin-3-yl)-1H-pyrazolo[4,3-c]pyridin-4- yl)methyl)carbamate (Preparationyl)amino)methyl)-5-methylpyridin- 181). 2-yl)-N-methylmethane-sulfonamide 100 N-(3-(((6-(4-(benzyloxy)-5-fluoro- MS m/z 853 [M + H]⁺2-(2,2,2-trifluoroethyl)phenyl)-3- Using 4-nitrophenyl ((2-(N-iodo-1-(tetrahydro-2H-pyran-2- ethylmethylsulfonamido)-5-yl)-1H-pyrazolo[-4,3-c]pyridin-4- methylpyridin-3-yl)methyl)carbamateyl)amino)-methyl)-5-methylpyridin- (Preparation 182).2-yl)-N-ethylmethane- sulfonamide 101 N-(2-(((6-(4-(benzyloxy)-5-fluoro-MS m/z 858 [M + H]⁺ 2-(2,2,2-trifluoroethyl)phenyl)-3- Using4-nitrophenyl {5-chloro-2- iodo-1-(tetrahydro-2H-pyran-2-[methyl(methylsulfonyl)amino]benzyl}carbamateyl)-1H-pyrazolo[4,3-c]pyridin-4- (Preparation 156). yl)amino)methyl)-4-chlorophenyl)-N-methylmethane- sulfonamide 102N-(2-(((6-(4-(benzyloxy)-5-fluoro- MS m/z 838 [M + H]⁺2-(2,2,2-trifluoroethyl)phenyl)-3- Using 4-nitrophenyl {2-iodo-1-(tetrahydro-2H-pyran-2-[ethyl(methylsulfonyl)amino]benzyl}carbamateyl)-1H-pyrazolo[4,3-c]pyridin-4- (Preparation 163).yl)amino)-methyl)-phenyl)-N- ethylmethane-sulfonamide 103N-(2-(((6-(4-(benzyloxy)-5-fluoro- MS m/z 854 [M + H]⁺2-(2,2,2-trifluoroethyl)phenyl)-3- Using 4-nitrophenyl {2-iodo-1-(tetrahydro-2H-pyran-2- [bis(methylsulfonyl)amino]-5-yl)-1H-pyrazolo[4,3-c]pyridin-4- methoxybenzyl}carbamateyl)amino)-methyl)-4- (Preparation 169). methoxyphenyl)-N-methylmethanesulfonamide 104 N-(2-(((6-(4-(benzyloxy)-5-fluoro- MS m/z852 [M + H]⁺ 2-(2,2,2-trifluoroethyl)phenyl)-3- Using 4-nitrophenyl {2-iodo-1-(tetrahydro-2H-pyran-2- [ethyl(methylsulfonyl)amino]-5-yl)-1H-pyrazolo-[4,3-c]pyridin-4- methylbenzyl}carbamateyl)amino)-methyl)-4-methyl- (Preparation 183). phenyl)-N-ethylmethanesulfonamide 105 N-methyl-N-(2-{[(6-[5-fluoro-2- MS m/z 910[M + H]⁺ (2,2,2-trifluoroethyl)-4-{[2- Using 4-nitrophenyl {2-(trimethylsilyl)- [methyl(methylsulfonyl)amino]benzyl}carbamateethoxy]methoxy}phenyl]-3-iodo- (Preparation 166). 1-{[2-(trimethylsilyl)ethoxy]methyl}-1H- pyrazolo[4,3-c]pyridin-4-yl)amino]-methyl}- phenyl)methane sulfonamide

The following Preparations (Preparations 106-109) were preparedaccording to the method described for Preparation 61 using6-[5-fluoro-4-methoxy-2-(2,2,2-trifluoroethyl)phenyl]-3-iodo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazolo[4,3-c]pyridine5-oxide (Preparation 111) or6-(2-cyclopropyl-5-fluoro-4-methoxyphenyl)-3-iodo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazolo[4,3-c]pyridine5-oxide (Preparation 115) and the appropriate aminocarbamate.

Preparation Number Name Data 106 N-(2-{[(6-[5-fluoro-4-methoxy-2- MS m/z886 [M + H]⁺ (2,2,2-trifluoroethyl)phenyl]-3- Using 4-nitrophenyl(2-{[(3- iodo-1-{[2-methoxyphenyl)sulfonyl](methyl)amino}benzyl)carbamate(trimethylsilyl)ethoxy]methyl}- (Preparation1H-pyrazolo[4,3-c]pyridin-4- 173). yl)amino]-methyl}phenyl)-3-methoxy-N- methylbenzenesulfonamide 107 N-ethyl-N-(2-{[(6-[5-fluoro-4-MS m/z 838 [M + H]⁺ methoxy-2-(2,2,2- Using 4-nitrophenyl {2-trifluoroethyl)phenyl]-3-iodo-1- [ethyl(methylsulfonyl)amino]-5-{[2-(trimethylsilyl)ethoxy]methyl}- methoxybenzyl}carbamate1H-pyrazolo[4,3-c]pyridin-4- (Preparation 174). yl)amino]-methyl}-4-methoxyphenyl)- methanesulfonamide 108 N-(2-{[(6-[5-fluoro-4-methoxy-2-MS m/z 886 [M + H]⁺ (2,2,2-trifluoroethyl)phenyl]-3- Using 4-nitrophenyl{5-methoxy-2- iodo-1-{[2- [methyl(phenylsulfonyl)amino]benzyl}(trimethylsilyl)ethoxy]methyl}- carbamate (Preparation 175).1H-pyrazolo[4,3-c]pyridin-4- yl)amino]-methyl}-4- methoxyphenyl)-N-methylbenzenesulfonamide 109 N-[2-({[6-(2-cyclopropyl-5-fluoro- MS m/z752 [M + H]+ 4-methoxyphenyl)-3-iodo-1-{[2- Using4-nitrophenyl{2-[methyl(methyl- (trimethylsilyl)ethoxy]methyl}-sulfonyl)amino]benzyl}carbamate 1H-pyrazolo[4,3-c]pyridin-4-(Preparation 166). yl]amino}methyl)phenyl]-N- methylmethanesulfonamide

Preparation 1106-(2-Cycloproyl-5-fluoro-4-methoxyphenyl)-N-methyl-4-[({2-[methyl(methylsulfonyl)-amino]pyridin-3-yl}methyl)amino]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazolo[4,3-c]pyridine-3-carboxamide

The title compound was prepared according to the method described forPreparation 61 using6-(2-cyclopropyl-5-fluoro-4-methoxyphenyl)-N-methyl-1-{[2-(trimethylsilyl)ethoxy]-methyl}-1H-pyrazolo[4,3-c]pyridine-3-carboxamide5-oxide (Preparation 116) and 4-nitrophenyl({2-[methyl(methylsulfonyl)amino]pyridin-3-yl}methyl)carbamate(Preparation 177). MS m/z 684 [M+H]⁺

Preparation 1116-[5-Fluoro-4-methoxy-2-(2,2,2-trifluoroethyl)phenyl]-3-iodo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazolo[4,3-c]pyridine5-oxide

To a stirred solution of6-[5-fluoro-4-methoxy-2-(2,2,2-trifluoroethyl)phenyl]-3-iodo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazolo[4,3-c]pyridine(Preparation 131, 5.50 g, 9.45 mmol) in dry DCM (550 mL) at 0° C., wasadded mCPBA (1.79 g, 10.40 mmol) portionwise followed by stirring atroom temperature for 16 hours. The reaction was quenched with saturatedaqueous sodium bicarbonate solution and saturated aqueous sodiumbisulphite solution, the organic extracts separated, dried and purifiedby silica gel column chromatography eluting with EtOAc to afford thetitle compound (3.40 g, 50%). ¹H NMR (400 MHz, DMSO-ds): δ ppm −0.12 (s,9H), 0.783 (m, 2H), 3.46-3.75 (m, 4H), 3.92 (s, 3H), 5.77 (m, 2H), 7.25(d, 1H), 7.36 (d, 1H), 8.13 (s, 1H), 8.63 (s, 1H). MS m/z 598 [M+H]⁺

Preparation 1126-[4-(Benzyloxy)-5-fluoro-2-(2,2,2-trifluoroethyl)phenyl]-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine5-oxide

To a stirred solution of6-[4-(benzyloxy)-5-fluoro-2-(2,2,2-trifluoroethyl)phenyl]-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine(Preparation 132, 17.7 g, 29 mmol) in anhydrous DCM (900 mL) at 0° C.was added mCPBA (7.51 g, 43.5 mmol) and the reaction was stirred warmingto room temperature for 18 hours. The reaction was quenched by theaddition of saturated sodium sulphite solution (600 mL) followed bysaturated aqueous sodium bicarbonate solution (600 mL). The organiclayer was collected, washed with water (3×50 mL), brine (2×50 mL), driedover sodium sulfate and concentrated in vacuo. The residue was purifiedusing silica gel column chromatography eluting with 56-80% EtOAc inhexanes to afford the title compound (13 g, 71%). ¹H NMR (400 MHz,DMSO-d₆): δ ppm 1.55-1.67 (m, 3H), 1.98 (m, 2H), 2.33 (m, 1H), 3.51 (m,1H), 3.68 (m, 2H), 3.88 (m, 1H), 5.28 (s, 2H), 5.90 (m, 1H), 7.30-7.51(m, 7H), 8.60 (s, 1H), 8.80 (s, 1H).

The following Preparations (Preparations 113-117) were preparedaccording to the method described for Preparation 111 using theappropriate pyrrolopyridine as described below:

Preparation Number Name Data 113 6-[5-fluoro-4-methoxy-2- MS m/z 598[M + H]⁺ (2,2,2-trifluoroethyl)- ¹H NMR (400 MHz, DMSO-d₆): δ ppmphenyl]-3-iodo-1-{[2- −0.147 (s, 9H), −0.02 (s, 9H), 0.78 (t, 2H), 0.92(t, (trimethylsilyl)- 2H), 0.97 (t, 2H), 2.31-2.49 (br m, 2H),ethoxy]methyl}-1H- 3.55 (br t, 2H), 3.78 (t, 2H), 5.35 (s, 1H), 5.74 (s,pyrazolo[4,3-c]pyridine 2H), 7.14 (d, 1H), 7.24 (d, 2H), 8.05 (s, 1H),5-oxide 8.59 (s, 1H). Using 6-(2-ethyl-5-fluoro-4-{[2-(trimethylsilyl)ethoxy]-methoxy}phenyl)-3-iodo-1-{[2-(trimethylsilyl)ethoxy]-methyl}-1H- pyrazolo[4,3-c]pyridine(Preparation 144). 114 6-[5-fluoro-2-(2,2,2- ¹H NMR (400 MHz, DMSO-d₆):δ ppm trifluoroethyl)-4-{[2- −0.11 (s, 9H), 0.00 (s, 9H), 0.78 (t, 2H),0.89 (t, 2H), (trimethylsilyl)ethoxy]methoxy}phenyl]- 3.52 (m, 3H),3.60-3.75 (m, 3H), 5.37 (m, 2H), 3-iodo-1- 5.71 (m, 2H), 7.31 (d, 1H),7.42 (d, 1H), {[2-(trimethyl- 8.14 (s, 1H), 8.64 (s, 1H).silyl)ethoxy]methyl}-1H- Using6-[5-fluoro-2-(2,2,2-trifluoroethyl)-4-{[2- pyrazolo[4,3-c]pyridine(trimethylsilyl)ethoxy]methoxy}phenyl]-3-iodo- 5-oxide1-{[2-(trimethylsilyl)ethoxy]methyl}-1H- pyrazolo[4,3-c]pyridine(Preparation 135). 115 6-(2-cyclopropyl-5- ¹H NMR (400 MHz, DMSO-d₆): δppm fluoro-4-methoxy- −0.11 (s, 9H), 0.64 (m, 4H), 0.81 (t, 2H), 1.71(m, phenyl)-3-iodo-1-{[2- 1H), 3.55 (t, 2H), 3.89 (s, 3H), 5.74 (s, 2H),(trimethylsilyl)ethoxy]- 6.78 (d, 1H), 7.14 (d, 1H), 8.06 (s, 1H),methyl}-1H-pyrazolo- 8.59 (s, 1H). [4,3-c]pyridine 5-oxide Using6-(2-cyclopropyl-5-fluoro-4- methoxyphenyl)-3-iodo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazolo[4,3- c]pyridine (Preparation136). 116 6-(2-cyclopropyl-5- MS m/z 487 [M + H]⁺ fluoro-4-methoxy- ¹HNMR (400 MHz, DMSO-d₆): δ ppm phenyl)-3-iodo-1-{[2- −0.10 (s, 9H), 0.64(m, 4H), 0.83 (t, 2H), 1.74 (m, (trimethyl-silyl)ethoxy]- 1H), 2.83 (d,3H), 3.58 (t, 2H), 3.89 (s, 3H), methyl}-1H-pyrazolo- 5.80 (s, 2H), 6.77(d, 1H), 7.13 (d, 1H), [4,3-c]pyridine 5-oxide 8.14 (s, 1H), 8.64 (m,1H), 8.95 (s, 1H). Using 6-(2-cyclopropyl-5-fluoro-4-methoxyphenyl)-N-methyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazolo[4,3- c]pyridine-3-carboxamide(Preparation 128). 117 6-[5-fluoro-2-(2,2,2-tri- MS m/z 645 [M + H]⁺fluoro-ethyl)-4-{[2-(tri- Using6-[5-fluoro-2-(2,2,2-trifluoroethyl)-4-{[2- methylsilyl)-ethoxy]-(trimethylsilyl)ethoxy]methoxy}phenyl]-N- methoxy}phenyl]-N-methyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H- methyl-1-{[2-pyrazolo[4,3-c]pyridine-3-carboxamide (trimethylsilyl)- (Preparation130). ethoxy]methyl}-1H- pyrazolo[4,3-c]pyridine- 3-carboxamide-5-oxide

Preparation 1184-Chloro-6-[5-fluoro-4-methoxy-2-(2,2,2-trifluoroethyl)phenyl]-N-methyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazolo[4,3-c]pyridine-3-carboxamide

Step 1

To a solution of6-[5-fluoro-4-methoxy-2-(2,2,2-trifluoroethyl)phenyl]-N-methyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazolo[4,3-c]pyridine-3-carboxamide(Preparation 125, 2 g, 3.90 mmol) in anhydrous DCM (30 mL) was addedmCPBA (1.2 g, 4.29 mmol) at 0° C. and the reaction was stirred at roomtemperature for 18 hours. The reaction was quenched by the addition ofsaturated aqueous sodium bisulfite and sodium bicarbonate solutions andextracted into DCM. The organic layer was collected, dried over sodiumsulfate and concentrated in vacuo. The residue was purified using silicagel column chromatography eluting with 15% MeOH in DCM to afford theintermediate N-oxide.

Step 2

This intermediate was dissolved in DMF (20 mL) and oxalyl chloride (2.43mL, 28.38 mmol) was added at 0° C. with stirring for 1 hour. Thereaction was quenched by the addition of water and extracted into EtOAc.The organic layer was collected, dried over sodium sulfate andconcentrated in vacuo. The residue was purified using silica gel columnchromatography eluting with 17% EtOAc in DCM to afford the titlecompound (400 mg, 26%). ¹H NMR (400 MHz, DMSO-d₆): δ ppm −0.11 (s, 9H),0.82 (m, 2H), 2.85 (d, 3H), 3.57 (t, 2H), 3.92 (s, 3H), 4.10 (q, 2H),5.85 (s, 2H), 7.37 (d, 1H), 7.49 (d, 1H), 8.11 (s, 1H), 8.69 (m, 1H). MSm/z 547 [M³⁵Cl+H]⁺

Preparation 1194-Chloro-6-[5-fluoro-4-methoxy-2-(2,2,2-trifluoroethyl)phenyl]-N-ethyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazolo[4,3-c]pyridine-3-carboxamide

The title compound was prepared according to the method described forPreparation 118 usingN-ethyl-6-[5-fluoro-4-methoxy-2-(2,2,2-trifluoroethyl)phenyl]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazolo[4,3-c]pyridine-3-carboxamide(Preparation 129).

MS m/z 561 [M+H]⁺

Preparation 120N-tert-Butyl-4-chloro-6-{5-fluoro-2-(2,2,2-trifluoroethyl)-4-{[2-(trimethylsilyl)ethoxy}-methoxy}phenyl]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazolo[4,3-c]pyridine-3-carboxamide

The title compound may be prepared according to the method described forPreparation 118, Step 1 usingN-tert-butyl-6-[5-fluoro-2-(2,2,2-trifluoroethyl)-4-{[2-(trimethylsilyl)ethoxy]methoxy}phenyl]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazolo[4,3-c]pyridine-3-carboxamide(Preparation 127). The N-oxide intermediate (1.3 g, 1.94 mmol) wasdissolved in DCM (150 mL) with triethylamine (0.35 mL, 2.52 mmol) andPOCl₃ (0.23 mL, 2.52 mmol) was added at 0° C. The reaction was stirredfor 1 hour at 10° C. before quenching with saturated aqueous sodiumbicarbonate solution and extraction with DCM. The organic layer wascollected, dried over sodium sulfate and concentrated in vacuo. Theresidue was purified using silica gel column chromatography eluting with15% EtOAc in DCM to afford a yellow oil (530 mg, 39%). ¹H NMR (400 MHz,DMSO-d₆): δ ppm −0.08 (s, 9H), −0.01 (s, 9H), 0.84 (t, 2H), 0.90 (t,2H), 1.41 (s, 9H), 3.58 (t, 2H), 3.77 (t, 2H), 4.07 (m, 2H), 5.37 (s,2H), 5.84 (s, 2H), 7.46 (m, 2H), 8.08 (s, 1H), 8.33 (s, 1H). MS m/z 705[M+H]⁺

Preparation 1214-Chloro-N-(2,4-dimethoxybenzyl)-6-[5-fluoro-4-methoxy-2-(2,2,2-trifluoroethyl)-phenyl]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazolo[4,3-c]pyridine-3-carboxamide

The title compound may be prepared according to the method described forPreparation 118 usingN-(2,4-dimethoxybenzyl)-6-[5-fluoro-4-methoxy-2-(2,2,2-trifluoroethyl)phenyl]-1-{[2-(trimethylsilyl)-ethoxy]methyl}-1H-pyrazolo[4,3-c]pyridine-3-carboxamide(Preparation 126). ¹H NMR (400 MHz, DMSO-d₆): δ ppm −0.10 (s, 9H), 0.85(t, 2H), 3.58 (t, 2H), 3.75 (s, 3H), 3.81 (s, 3H), 3.92 (s, 3H), 4.09(q, 2H), 4.43 (m, 2H), 5.85 (s, 2H), 6.50 (m, 1H), 6.58 (s, 1H), 7.24(d, 1H), 7.35 (d, 1H), 7.49 (d, 1H), 8.11 (s, 1H), 8.97 (m, 1H). MS m/z683 [M+H]⁺

Preparation 1224-Chloro-6-[5-fluoro-2-(2,2,2-trifluoroethyl)-4-{[2-(trimethylsilyl)ethoxy]methoxy}phenyl]-N-methyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazolo[4,3-c]pyridine-3-carboxamide

The title compound may be prepared according to the method described forPreparation 118 using6-[5-fluoro-2-(2,2,2-trifluoroethyl)-4-{[2-(trimethylsilyl)ethoxy]methoxy}phenyl]-N-methyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazolo[4,3-c]pyridine-3-carboxamide(Preparation 130). The N-oxide intermediate (800 mg, 1.24 mmol) wasdissolved in DCM (7 mL) and a solution of POCl₃ (0.148 mL, 1.6 mmol) inDCM (3 mL) was added dropwise at 0° C. The reaction was stirred for 30minutes before the addition of water and extraction into DCM. Theorganic layer was collected, dried over sodium sulfate and concentratedin vacuo. The residue was purified using silica gel columnchromatography eluting with 14% EtOAc in DCM to afford the titlecompound as a yellow solid (600 mg, 73%).

¹H NMR (400 MHz, DMSO-d₆): δ ppm −0.11 (s, 9H), −0.01 (s, 9H), 0.82 (t,2H), 0.90 (t, 3H), 2.85 (d, 3H), 3.57 (t, 2H), 3.77 (t, 2H), 5.37 (s,2H), 5.85 (s, 2H), 7.43-7.51 (m, 2H), 8.11 (s, 1H), 8.67 (m, 1H). MS m/z629 [M+H]⁺

Preparation 1236-(4-(Benzyloxy)-5-fluoro-2-(2,2,2-trifluoroethyl)phenyl)-N-(tert-butyl)-4-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide

To a solution of6-(4-(benzyloxy)-5-fluoro-2-(2,2,2-trifluoroethyl)phenyl)-N-(tert-butyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide(Preparation 124, 3.80 g, 6.5 mmol) in anhydrous DCM (250 mL) was addedmCPBA (1.68 g, 9.75 mol) at 0° C. and the reaction was stirred at roomtemperature for 18 hours. The reaction was quenched by the addition ofsaturated aqueous sodium sulphite solution and saturated aqueous sodiumbicarbonate solution and extracted into EtOAc. The organic layer wascollected, dried over sodium sulfate and concentrated in vacuo. Theresidue was purified using silica gel column chromatography eluting withEtOAc to afford the intermediate N-oxide, that was dissolved in DCM (300mL). To the solution was added triethylamine (1.07 mL, 7.74 mmol)followed by POCl₃ (0.62 mL, 6.71 mmol) at 0° C. The reaction was stirredat 10° C. for 1 hour before the addition of ice-water. The reaction wasextracted into DCM, the organic layer was collected, dried over sodiumsulfate and concentrated in vacuo to afford the title compound as thedesired chloro isomer confirmed by nOe irradiation of the remainingpyridyl proton.

¹H NMR (400 MHz, DMSO-d₆): δ ppm 1.41 (s, 9H), 1.56-1.80 (m, 3H),1.95-2.04 (m, 2H), 2.37 (m, 1H), 3.76 (m, 1H), 3.91-4.18 (m, 3H), 5.27(s, 2H), 6.01 (m, 1H), 7.34-7.55 (m, 7H), 8.03 (s, 1H), 8.38 (br s, 1H).MS m/z 619 [M+H]⁺

Preparation 1246-(4-(Benzyloxy)-5-fluoro-2-(2,2,2-trifluoroethyl)phenyl)-N-(tert-butyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide

To a solution of6-[4-(benzyloxy)-5-fluoro-2-(2,2,2-trifluoroethyl)phenyl]-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine(Preparation 132, 8 g, 13 mmol) in THF (30 mL) and tert-butylamine (16mL) was added molybdenum hexacarbonyl (3.48 g, 13 mmol), DBU (5.86 mL,39.25 mmol) and Pd(OAc)₂ (180 mg, 1.3 mmol). The reaction was heated ina sealed tube at 100° C. for 1 hour. The reaction was cooled,concentrated in vacuo and purified using silica gel columnchromatography to afford the title compound. ¹H NMR (400 MHz, DMSO-d₆):δ ppm 1.46 (s, 9H), 1.60-1.74 (m, 4H), 1.97-2.01 (m, 2H), 3.76-3.82 (m,1H), 3.94-4.22 (m, 3H), 5.27 (s, 2H), 6.03 (m, 1H), 7.36-7.52 (m, 7H),7.60 (m, 1H), 8.01 (m, 1H), 9.41 (s, 1H). MS m/z 585 [M+H]⁺

Preparation 1256-[5-Fluoro-4-methoxy-2-(2,2,2-trifluoroethyl)phenyl]-N-methyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazolo[4,3-c]pyridine-3-carboxamide

To a solution of6-[5-fluoro-4-methoxy-2-(2,2,2-trifluoroethyl)phenyl]-3-iodo-1-{([2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazolo[4,3-c]pyridine(Preparation 131, 3.4 g, 5.85 mmol) and 2M methylamine in THF (30 mL)was added palladium acetate (92 mg, 0.41 mmol), DBU (2.62 mL, 17.54mmol) and molybdenum hexacarbonyl (1.55 g, 5.85 mmol). The reaction washeated in a sealed tube at 100° C. for 60 minutes before concentratingin vacuo. The residue was diluted with EtOAc, filtered through celiteand concentrated in vacuo. The residue was purified using silica gelcolumn chromatography eluting with 30% EtOAc in hexanes to afford thetitle compound as a yellow solid (2 g, 67%). ¹H NMR (400 MHz, DMSO-d₆):δ ppm −0.15 (s, 9H), 0.80 (t, 2H), 2.85 (d, 3H), 3.56 (t, 2H), 3.92 (s,3H), 4.18 (q, 2H), 5.87 (s, 2H), 7.33 (d, 1H), 7.41 (d, 1H), 8.07 (s,1H), 8.66 (m, 1H), 9.45 (s, 1H). MS m/z 513 [M+H]⁺

The following Preparations (Preparations 126-129) were preparedaccording to the method described for Preparation 125 using theappropriate pyrrolopyridine and amine as described below:

Preparation Number Name Data 126 N-(2,4-dimethoxybenzyl)- MS m/z 649[M + H]⁺ 6-[5-fluoro-4-methoxy-2- Using 6-[5-fluoro-4-methoxy-2-(2,2,2-(2,2,2- trifluoroethyl)phenyl]-3-iodo-1-{[2-trifluoroethyl)phenyl]-1-{[2- (trimethylsilyl)ethoxy]methyl}-1H-(trimethylsilyl)ethoxy]methyl}- pyrazolo[4,3-c]pyridine (Preparation131) 1H-pyrazolo[4,3- and 2,4-dimethoxybenzylamine.c]pyridine-3-carboxamide 127 N-tert-butyl-6-[5-fluoro-2- MS m/z 671 [M +H]⁺ (2,2,2-trifluoroethyl)-4-{[2- ¹H NMR (400 MHz, DMSO-d₆): δ ppm(trimethylsilyl)- −0.13 (s, 9H), −0.01 (s, 9H), 0.81 (t, 2H), 0.91 (t,ethoxy]methoxy}phenyl]-1- 2H), 1.45 (s, 9H), 3.58 (t, 2H), 3.80 (t, 2H),{[2-(trimethylsilyl)- 4.03 (m, 2H), 5.36 (s, 2H), 6.02 (s, 2H),ethoxy]methyl}-1H- 7.43 (m, 2H), 7.66 (s, 1H), 8.08 (s, 1H).pyrazolo[4,3-c]pyridine-3- Using 6-[5-fluoro-2-(2,2,2-trifluoroethyl)-4-carboxamide {[2-(trimethylsilyl)ethoxy]methoxy}phenyl]-3-iodo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H- pyrazolo[4,3-c]pyridine(Preparation 135) and tert-butylamine. 128 6-(2-cyclopropyl-5-fluoro-Taken on directly to the next step. 4-methoxyphenyl)-N- Using6-(2-cyclopropyl-5-fluoro-4- methyl-1-{[2-methoxyphenyl)-3-iodo-1-{[2-(trimethylsilyl)-(trimethylsilyl)ethoxy]methyl}-ethoxy]methyl}-1H-pyrazolo[4,3-c]pyridine 1H-pyrazolo[4,3- (Preparation136) and methylamine. c]pyridine-3-carboxamide 129N-ethyl-6-[5-fluoro-4- ¹H NMR (400 MHz, DMSO-d₆): δ ppmmethoxy-2-(2,2,2- −0.14 (s, 9H), 0.80 (t, 2H), 1.17 (t, 3H), 3.37 (m,trifluoroethyl)phenyl]-1-{[2- 2H), 3.56 (t, 2H), 3.89 (s, 3H), 4.18 (m,2H), (trimethylsilyl)ethoxy]methyl}- 5.87 (s, 2H), 7.33 (d, 1H), 7.44(d, 1H), 1H-pyrazolo[4,3- 8.08 (s, 1H), 8.72 (m, 1H), 9.45 (s, 1H).c]pyridine-3-carboxamide Using 6-[5-fluoro-4-methoxy-2-(2,2,2-trifluoroethyl)phenyl]-3-iodo-1-{[2- (trimethylsilyl)-ethoxy]methyl}-1H-pyrazolo[4,3-c]pyridine (Preparation 131) with ethylamine.

Preparation 1306-[5-Fluoro-2-(2,2,2-trifluoroethyl)-4-{[2-(trimethylsilyl)ethoxy]methyl}phenyl]-N-methyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazolo[4,3-c]pyridine-3-carboxamide

The title compound may be prepared according to the method described forPreparation 18 using6-[5-fluoro-2-(2,2,2-trifluoroethyl)-4-{[2-(trimethylsilyl)ethoxy]-methoxy}phenyl]-3-iodo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazolo[4,3-c]pyridine(Preparation 135) with methylamine. ¹H NMR (400 MHz, DMSO-d₆): δ ppm−0.15 (s, 9H), −0.01 (s, 9H), 0.80 (t, 2H), 0.91 (t, 2H), 2.85 (d, 3H),3.58 (t, 2H), 3.78 (t, 2H), 4.10 (q, 2H), 5.36 (s, 2H), 5.87 (s, 2H),7.43 (m, 2H), 8.08 (s, 1H), 8.64 (m, 1H), 9.46 (s, 1H). MS m/z 629[M+H]⁺

Preparation 1316-[5-Fluoro-4-methoxy-2-(2,2,2-trifluoroethyl)phenyl]-3-iodo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazolo[4,3-c]pyridine

To a suspension of NaH (0.59 g, 24.93 mmol) in dry DMF (100 mL) at 0° C.was added a solution of6-[5-fluoro-4-methoxy-2-(2,2,2-trifluoroethyl)phenyl]-3-iodo-1H-pyrazolo[4,3-c]pyridine(Preparation 137, 7.50 g, 16.62 mmol) in DMF (100 mL). The reaction wasstirred for 30 minutes before the addition of SEM-chloride (4.42 mL,24.93 mmol) drop-wise. The reaction was stirred for 1 hour before beingquenched with ice-water and extracted into EtOAc. The organic layer waswashed with water, brine, dried over sodium sulfate and concentrated invacuo. The crude residue was purified using silica gel columnchromatography to afford the title compound as a yellow liquid (5.50 g,47%). ¹H NMR (400 MHz, DMSO-d₆): δ ppm −0.15 (s, 9H), 0.76 (m, 2H), 3.51(m, 2H), 3.91 (s, 3H), 4.11 (q, 2H), 5.81 (s, 2H), 7.33 (d, 1H), 7.42(d, 1H), 7.99 (s, 1H), 8.85 (s, 1H). MS m/z 582 [M+H]⁺

Preparation 1326-[4-(Benzyloxy)-5-fluoro-2-(2,2,2-trifluoroethyl)phenyl]-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine

To a solution of2-fluoro-4-[3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl]-5-(2,2,2-trifluoroethyl)phenol(Preparation 133, 21.8 g, 41.8 mmol) in acetone (200 mL) was treatedwith benzyl bromide (7.5 mL, 62.7 mmol) and potassium carbonate (14.4 g,104 mmol) and the reaction was heated to reflux. The reaction wascooled, filtered, the filtrate collected and concentrated in vacuo. Theresidue was taken up in EtOAc, washed with water, brine, dried oversodium sulfate and concentrated in vacuo. The residue was purified usingsilica gel column chromatography eluting with 18% EtOAc in hexane toafford the title compound (23 g, 90%).

¹H NMR (400 MHz, DMSO-d₆): δ ppm 1.57-1.71 (m, 3H), 2.01 (m, 2H), 2.37(m, 1H), 3.74 (m, 1H), 3.91 (m, 1H), 4.03 (m, 1H), 4.16 (m, 1H), 5.27(s, 2H), 5.97 (m, 1H), 7.34-7.51 (m, 7H), 7.95 (s, 1H), 8.83 (s, 1H). MSm/z 612 [M+H]⁺

Preparation 1332-Fluoro-4-[3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl]-5-(2,2,2-trifluoroethyl)phenol

To a solution of2-fluoro-4-(3-iodo-1H-pyrazolo[4,3-c]pyridin-6-yl)-5-(2,2,2-trifluoroethyl)phenol(Preparation 134, 40.8 g, 93 mmol) in DMF (500 mL) was addeddihydropyran (17 mL, 187 mmol) and PTSA (7.10 g, 37 mmol) and thereaction was heated to 80° C. for 18 hours. Additional dihydropyran (2eq) and PTSA (0.4 eq) were added and the reaction continued at thistemperature for a further 2 hours followed by cooling to roomtemperature for 18 hours. The reaction was quenched by the addition ofsaturated aqueous sodium bicarbonate solution dropwise, and concentratedin vacuo. The aqueous residue was extracted into EtOAc, washed withwater, brine, dried over sodium sulfate and concentrated in vacuo. Theresidue was purified using silica gel column chromatography eluting with17-20% EtOAc in hexanes to afford the title compound as a yellow solid(22 g, 45%). ¹H NMR (400 MHz, DMSO-d₆): δ ppm 1.44-1.70 (m, 3H), 2.02(m, 2H), 2.37 (m, 1H), 3.75 (m, 1H), 3.88-4.06 (m, 2H), 4.15 (m, 1H),5.97 (m, 1H), 7.10 (d, 1H), 7.40 (d, 1H), 7.91 (s, 1H), 8.81 (s, 1H),10.31 (s, 1H). MS m/z 522 [M+H]⁺

Preparation 1342-Fluoro-4-(3-iodo-1H-pyrazolo[4,3-c]pyridin-6-yl)-5-(2,2,2-trifluoroethyl)phenol

A solution of6-[5-fluoro-4-methoxy-2-(2,2,2-trifluoroethyl)phenyl]-3-iodo-1H-pyrazolo[4,3-c]pyridine(Preparation 137, 44 g, 97 mmol) in DCM (350 mL) was treated with borontribromide (46 mL, 488 mmol) at 0° C., and the reaction was allowed tostir warming to room temperature over 5 hours. The reaction wasconcentrated in vacuo and treated with saturated aqueous sodiumbicarbonate solution. The resulting precipitate was filtered and driedunder vacuum to afford the title compound as a white solid (41 g, 97%).¹H NMR (400 MHz, DMSO-d₆): δ ppm 4.00 (q, 2H), 7.09 (d, 1H), 7.37 (d,1H), 7.58 (s, 1H), 8.81 (s, 1H), 10.26 (s, 1H), 13.95 (s, 1H). MS m/z438 [M+H]⁺

Preparation 1356-[5-Fluoro-2-(2,2,2-trifluoroethyl)-4-{[2-(trimethylsilyl)ethoxy]methoxy}phenyl]-3-iodo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazolo[4,3-c]pyridine

The title compound was prepared according to the method described forPreparation 131 using6-[4-{[tert-butyl(dimethyl)silyl]oxy}-5-fluoro-2-(2,2,2-trifluoroethyl)phenyl]-3-iodo-1H-pyrazolo[4,3-c]pyridine(Preparation 138). The reaction conditions cause deprotection of theTBDMS ether and subsequent re-protection with SEM-chloride. ¹H NMR (400MHz, DMSO-d₆): δ ppm −0.14 (s, 9H), −0.03 (s, 9H), 0.78 (t, 2H), 0.90(t, 2H), 3.56 (t, 2H), 3.77 (t, 2H), 4.09 (m, 2H), 5.36 (s, 2H), 5.81(s, 2H), 7.42 (m, 2H), 8.01 (s, 1H), 8.86 (s, 1H). MS m/z 698 [M+H]⁺

Preparation 1366-(2-Cyclopropyl-5-fluoro-4-methoxyphenyl)-3-iodo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazolo[4,3-c]pyridine

The title compound was prepared according to the method described forPreparation 131 using6-(2-cyclopropyl-5-fluoro-4-methoxyphenyl)-3-iodo-1H-pyrazolo[4,3-c]pyridine(Preparation 139). Taken on to the next step without furtherpurification.

Preparation 1376-[5-Fluoro-4-methoxy-2-(2,2,2-trifluoroethyl)phenyl]-3-iodo-1H-pyrazolo[4,3-c]pyridine

To a solution of6-[5-fluoro-4-methoxy-2-(2,2,2-trifluoroethyl)phenyl]-1H-pyrazolo[4,3-c]pyridine(Preparation 140, 11.20 g, 34.43 mmol) in DMF (200 mL) at 0° C. wasadded N-iodosuccinimide (9.29 g, 41.32 mmol). The reaction was stirredat room temperature for 16 hours. The reaction was diluted with ethylacetate, washed with saturated aqueous sodium bicarbonate solution andsaturated aqueous sodium thiosulfate solution. The organic extracts wereseparated, washed with brine, dried over sodium sulfate and concentratedin vacuo. The residue was purified by silica gel column chromatographyeluting with 22% EtOAc in hexanes to afford the title compound as awhite solid (7.50 g, 48%). ¹H NMR (400 MHz, DMSO-d₆): δ ppm 3.91 (s,3H), 4.11 (q, 2H), 7.32 (d, 1H), 7.46 (d, 1H), 7.62 (s, 1H), 8.83 (s,1H), 13.90 (br s, 1H). MS m/z 452 [M+H]⁺

Preparation 1386-[4-{[tert-Butyl(dimethyl)silyl]oxy}-5-fluoro-2-(2,2,2-trifluoroethyl)phenyl]-3-iodo-1H-pyrazolo[4,3-c]pyridine

The title compound was prepared according to the method described forPreparation 137 using6-[4-{[tert-butyl(dimethyl)silyl]oxy}-5-fluoro-2-(2,2,2-trifluoroethyl)phenyl]-1H-pyrazolo-[4,3-c]pyridine(Preparation 141). ¹H NMR (400 MHz, DMSO-d₆): δ ppm 0.24 (s, 6H), 0.99(s, 9H), 4.08 (m, 2H), 7.16 (d, 1H), 7.46 (d, 1H), 7.65 (s, 1H), 8.83(s, 1H), 13.99 (br s, 1H). MS m/z 552 [M+H]⁺

Preparation 1396-(2-Cyclopropyl-5-fluoro-4-methoxyphenyl)-3-iodo-1H-pyrazolo[4,3-c]pyridine

The title compound was prepared according to the method described forPreparation 137 using6-(2-cyclopropyl-5-fluoro-4-methoxyphenyl)-1H-pyrazolo[4,3-c]pyridine(Preparation 143). The residue was triturated with pentane and ether. ¹HNMR (400 MHz, DMSO-d₆): δ ppm 0.69 (m, 2H), 0.80 (m, 2H), 2.09 (m, 1H),3.88 (s, 3H), 6.73 (d, 1H), 7.30 (d, 1H), 7.65 (s, 1H), 8.83 (s, 1H),13.88 (s, 1H).

Preparation 1406-[5-Fluoro-4-methoxy-2-(2,2,2-trifluoroethyl)phenyl]-1H-pyrazolo[4,3-c]pyridine

To a solution of6-[5-fluoro-4-methoxy-2-(2,2,2-trifluoroethyl)phenyl]-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine(Preparation 145, 14.50 g, 35.41 mmol) in dioxane (150 mL) was added 4MHCl in dioxane (60 mL). The reaction was stirred at room temperature for16 hours before concentrating in vacuo. The residue was partitionedbetween EtOAc and saturated aqueous sodium bicarbonate solution. Theorganic layer was collected, washed with brine, dried over sodiumsulfate and concentrated in vacuo to afford the title compound that wasused directly in the next reaction (11.20 g, 97%). MS m/z 326 [M+H]⁺

Preparation 1416-[4-{[tert-Butyl(dimethyl)silyl]oxy}-5-fluoro-2-(2,2,2-trifluoroethyl)phenyl]-1H-pyrazolo[4,3-c]pyridine

To a solution of2-fluoro-4-(1H-pyrazolo[4,3-c]sulfate-6-yl)-5-(2,2,2-trifluoroethyl)phenol(Preparation 142, 13 g, 41.76 mmol) and 2,6 lutidine (7.29 mL, 62.65mmol) in anhydrous THF (500 mL) at 0° C. was added TBDMS-triflate (11.52mL, 50.12 mmol) and the reaction was stirred at room temperature for 18hours. The reaction was concentrated in vacuo and partitioned betweenwater and ethyl acetate. The organic layer was collected, washed withbrine, dried over sodium sulfate and concentrated in vacuo. The residuewas purified by silica gel column chromatography eluting with 20% EtOAcin hexanes to afford the title compound as a white solid (11 g, 62%). ¹HNMR (400 MHz, DMSO-d₆): δ ppm 0.24 (s, 6H), 0.99 (s, 9H), 4.09 (m, 2H),7.17 (d, 1H), 7.45 (d, 1H), 7.63 (s, 1H), 8.33 (s, 1H), 9.15 (s, 1H),13.57 (br s, 1H).

Preparation 1422-Fluoro-4-(1H-pyrazolo[4,3-c]pyridin-6-yl)-5-(2,2,2-trifluoroethyl)phenol

6-[5-fluoro-2-(2,2,2-trifluoroethyl)-4-{[2-(trimethylsilyl)ethoxy]methoxy}phenyl]-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine(Preparation 146, 24 g, 45.66 mmol) was dissolved in TFA (48 mL) at 0°C. and stirred for 1 hour. The reaction was concentrated in vacuo andtaken up in MeOH. Ethylene diamine (2.4 mL) was added at 0° C. and thereaction stirred for 20 minutes. The reaction was concentrated in vacuoand partitioned between IPA:DCM (1:9) and water. The organic extract wasdried with sodium sulfate and concentrated in vacuo. The residue waspurified by silica gel column chromatography to afford the titlecompound as an off-white solid (13 g, 91%). ¹H NMR (400 M₃ Hz, DMSO-d₆):δ ppm 3.98 (m, 2H), 7.08 (d, 1H), 7.33 (d, 1H), 7.57 (s, 1H), 8.32 (s,1H), 9.14 (s, 1H), 10.21 (brs, 1H), 13.52 (brs, 1H).

Preparation 1436-(2-Cyclopropyl-5-fluoro-4-methoxyphenyl)-1H-pyrazolo[4,3-c]pyridine

To a solution of6-(2-cyclopropyl-5-fluoro-4-methoxyphenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine(Preparation 148, 5 g, 13.61 mmol) in MeOH (25 mL) was addedconcentrated HCl (3.5 mL) at 0° C. and the reaction was stirred for 16hours. The reaction was concentrated in vacuo and partitioned betweensaturated aqueous NaHCO₃ solution and 25% IPA in DCM. The organic layerwas collected, dried over sodium sulfate and concentrated in vacuo toafford the title compound as a white solid (3.3 g, 85%). ¹H NMR (400MHz, DMSO-d₆): δ ppm 0.71 (m, 2H), 0.81 (m, 2H), 2.12 (m, 1H), 3.88 (s,3H), 6.71 (d, 1H), 7.30 (d, 1H), 7.66 (s, 1H), 8.32 (s, 1H), 9.16 (s,1H), 13.46 (s, 1H). MS m/z 284 [M+H]⁺

Preparation 1446-(2-Ethyl-5-fluoro-4-{[2-(trimethylsilyl)ethoxy]methoxy}phenyl)-3-iodo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazolo[4,3-c]pyridine

The title compound was prepared according to the methods described byPreparations 142, 141, 137 and 131 using6-[2-ethyl-5-fluoro-4-{[2-(trimethylsilyl)ethoxy]methoxy}phenyl]-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine(Preparation 147). ¹H NMR (400 MHz, DMSO-d₆): δ ppm −0.13 (s, 9H), −0.01(s, 9H), 0.79 (t, 2H), 0.91 (t, 2H), 0.99 (t, 2H), 2.66 (q, 2H), 3.55(t, 2H), 3.78 (t, 2H), 5.35 (s, 2H), 5.80 (s, 2H), 7.22 (m, 2H), 7.88(s, 1H), 8.84 (s, 1H).

Preparation 1456-[5-Fluoro-4-methoxy-2-(2,2,2-trifluoroethyl)phenyl]-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine

A solution of palladium acetate (0.47 g, 2.10 mmol) and S-Phos (0.86 g,2.10 mmol) in ethanol (75 mL) was heated at 50° C. for 45 minutes afterpurging with nitrogen (Solution A). Meanwhile a solution of6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine(Preparation 149, 10 g, 42.07 mmol) in ethanol (75 mL) was treated with2-[5-fluoro-4-methoxy-2-(2,2,2-trifluoroethyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(WO20131014567A1, 21.08 g, 63.10 mmol) and an aqueous solution ofpotassium phosphate (17.86 g, 84.14 mmol) in water (50 mL) followed bypurging with nitrogen for 10 minutes (Solution B). Solution A was addedto Solution B and the reaction heated to 80° C. for 18 hours beforecooling and concentrating in vacuo. The residue was partitioned betweenethyl acetate and water, the organic extracts collected, washed withbrine, dried over sodium sulfate and concentrated in vacuo. The residuewas purified using silica gel column chromatography eluting with 15%EtOAc in hexanes to afford the title compound as a yellow liquid (14.10g, 82%). ¹H NMR (400 MHz, DMSO-ds): δ ppm 1.58 (m, 2H), 1.73 (m, 1H),1.99 (m, 2H), 2.42 (m, 1H), 3.78 (m, 1H), 3.92 (m, 4H), 4.09 (m, 1H),4.26 (m, 1H), 5.98 (d, 1H), 7.33 (d, 1H), 7.48 (d, 1H), 7.92 (s, 1H),8.37 (s, 1H), 9.15 (s, 1H). MS m/z 410 [M+H]⁺

Preparation 1466-[5-Fluoro-2-(2,2,2-trifluoroethyl)-4-{[2-(trimethylsilyl)ethoxy]methoxy}phenyl]-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine

The title compound was prepared according to the method described forPreparation 145 using6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine(Preparation 149) and(2-{[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(2,2,2-trifluoroethyl)phenoxy]methoxy}ethyl)(trimethyl)silane(Preparation 150). The residue was purified using silica gel columnchromatography eluting with 9% EtOAc in hexanes (19 g, 86%). ¹H NMR (400MHz, DMSO-d₆): δ ppm −0.02 (s, 9H), 0.91 (m, 2H), 1.58 (m, 2H), 1.73 (m,1H), 2.05 (m, 2H), 2.41 (m, 1H), 3.73 (m, 2H), 3.92-4.21 (m, 2H), 5.35(s, 2H), 5.98 (m, 1H), 7.40 (d, 1H), 7.50 (d, 1H), 7.93 (s, 1H), 8.38(s, 1H), 9.16 (s, 1H).

Preparation 1476-[2-Ethyl-5-fluoro-4-{[2-(trimethylsilyl)ethoxy]methoxy}phenyl]-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine

The title compound was prepared according the method described forPreparation 145 using(2-{[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-ethyl-phenoxy]methoxy}ethyl)(trimethyl)silane(WO20131014567A1) and6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine(Preparation 149). The residue was purified using silica gel columnchromatography eluting with 30% EtOAc in hexanes (34 g, 85%). ¹H NMR(400 MHz, DMSO-d₆): δ ppm 0.01 (s, 9H), 0.92 (m, 2H), 1.05 (m, 3H), 1.58(m, 2H), 1.73 (m, 1H), 2.03 (m, 2H), 2.41 (m, 1H), 2.65 (m, 2H),3.72-3.92 (m, 4H), 5.34 (s, 2H), 5.93 (m, 1H), 7.21-7.28 (m, 2H), 7.80(s, 1H), 8.36 (s, 1H), 9.14 (s, 1H). MS m/z 526 [M+H]⁺

Preparation 1486-(2-Cyclopropyl-5-fluoro-4-methoxyphenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine

The title compound was prepared according the method described forPreparation 145 using2-(2-cyclopropyl-5-fluoro-4-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(Preparation 151) and6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine(Preparation 149). ¹H NMR (400 MHz, DMSO-d₆): δ ppm 0.65-0.85 (m, 4H),1.58 (m, 2H), 1.71 (m, 1H), 2.01 (m, 2H), 2.11 (m, 1H), 2.40 (m, 1H),3.31 (s, 3H), 3.74 (m, 1H), 3.90 (m, 1H), 5.94 (m, 1H), 6.74 (d, 1H),7.31 (d, 1H), 7.91 (s, 1H), 8.35 (s, 1H), 9.15 (s, 1H). MS m/z 368[M+H]⁺

Preparation 1496-Chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine

To a solution of 6-chloro-1H-pyrazolo[4,3-c]pyridine (75 g, 488.37 mmol)in DCM (2 L) was added dihydropyran (66.98 mL, 732.56 mmol) followed bypara-toluenesulfonic acid (18.58 g, 97.67 mmol) and the reaction washeated to reflux for 18 hours. Further para-toluenesulfonic acid (0.1eq) and dihydropyran (0.75 eq) were added and the reaction continuedheating at reflux for 6 hours. The reaction was cooled and quenched withsaturated aqueous sodium bicarbonate solution. The organic layer wascollected, washed with brine, dried over sodium sulfate and concentratedin vacuo. The residue was purified using silica gel columnchromatography eluting with 17% EtOAc in hexanes followed by triturationwith ether to afford the title compound as a pale yellow solid (83 g,72%). ¹H NMR (400 MHz, DMSO-d₆): δ ppm 1.59 (m, 2H), 1.71 (m, 1H), 2.02(m, 2H), 2.29 (m, 1H), 3.74 (m, 1H), 3.89 (m, 1H), 5.91 (m, 1H), 7.93(s, 1H), 8.38 (s, 1H), 8.94 (s, 1H).

Preparation 150(2-{[2-Fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(2,2,2-trifluoroethyl)phenoxy]methoxy}ethyl)(trimethyl)silane

To a solution of(2-{[4-bromo-2-fluoro-5-(2,2,2-trifluoroethyl)phenoxy]methoxy}ethyl)-(trimethyl)silane(Preparation 152, 34 g, 84.31 mmol), in dry 1,4-dioxane (1 L) was addedbis(pinacolonato)diboron (21.41 g, 84.31 mmol) followed by KOAc (24.82g, 252.95 mmol). The reaction mixture was purged with nitrogen for 20minutes before the addition of Pd(dppf)₂Cl₂ (6.886 g, 8.432 mmol)followed by further degassing for 20 minutes. The reaction was heated toreflux for 18 hours before cooling to room temperature and concentratingin vacuo. The residue was suspended in EtOAc and filtered through a bedof Celite. The filtrate was washed with water, dried over sodium sulfateand concentrated in vacuo. The residue was purified using silica gelcolumn chromatography eluting with 10% EtOAc in hexanes to afford thetitle compound as an oil (31 g, 82%). ¹H NMR (400 MHz, DMSO-d₆): δ ppm−0.05 (s, 9H), 0.87 (m, 2H), 1.32 (s, 12H), 3.74 (m, 2H), 3.92 (m, 2H),5.32 (s, 2H), 7.29 (d, 1H), 7.42 (d, 1H).

Preparation 1512-(2-Cyclopropyl-5-fluoro-4-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

The title compound was prepared according to the method described forPreparation 150 using 1-bromo-2-cyclopropyl-5-fluoro-4-methoxybenzene(Preparation 154). Taken on to the next step as is.

Preparation 152(2-{[4-Bromo-2-fluoro-5-(2,2,2-trifluoroethyl)phenoxy]methoxy}ethyl)(trimethyl)silane

To a solution of 4-bromo-2-fluoro-5-(2,2,2-trifluoroethyl)phenol(Preparation 153, 25 g, 91.57 mmol) in DCM (200 mL) was added DIPEA(17.54 mL, 100.73 mmol) at room temperature followed by SEM-Cl (17.86mL, 100 mmol) drop-wise at 0° C. and the reaction was stirred at roomtemperature for 4 hours. The reaction was partitioned between DCM andwater, the organic layer was collected, washed with brine, dried oversodium sulfate and concentrated in vacuo to afford the title compound asan oil (34 g, 92%). ¹H NMR (400 MHz, DMSO-d₆): δ ppm −0.03 (s, 9H), 0.87(m, 2H), 3.70-3.79 (m, 4H), 5.29 (s, 2H), 7.42 (d, 1H), 7.70 (d, 1H).

Preparation 153 4-Bromo-2-fluoro-5-(2,2,2-trifluoroethyl)phenol

To a solution of1-bromo-5-fluoro-4-methoxy-2-(2,2,2-trifluoroethyl)benzene(WO20131014567A1, 30 g, 104.51 mmol) in DCM (800 mL) at 0° C. was addedboron tribromide (130.91 g, 522 mmol) drop-wise and the reaction wasstirred at room temperature for 16 hours. The reaction was quenched bythe addition of saturated aqueous NaHCO₃ solution and extracted intoDCM. The organic layer was collected, washed with brine, dried oversodium sulfate and concentrated in vacuo to afford the title compound asa white solid that was taken directly on to the next step (22 g, 77%).

Preparation 154 1-Bromo-2-cyclopropyl-5-fluoro-4-methoxybenzene

To a solution of 4-cyclopropyl-1-fluoro-2-methoxybenzene (Preparation155, 8.7 g, 41 mmol) in DMF (250 mL) at 0° C. was added NBS (7.40 g, 41mmol) and the reaction was stirred at room temperature for 3 hours. Thereaction was partitioned between EtOAc and brine, the organic layer wascollected, dried over sodium sulfate and concentrated in vacuo. Theresidue was purified using silica gel column chromatography eluting withhexanes to afford the title compound as a colorless oil (9.5 g, 92%). ¹HNMR (400 MHz, DMSO-d₆): δ ppm 0.73 (m, 2H), 0.96 (m, 2H), 2.01 (m, 1H),3.82 (s, 3H), 6.72 (d, 1H), 7.50 (d, 1H).

Preparation 155 4-Cyclopropyl-1-fluoro-2-methoxybenzene

To a solution of 5-bromo-2-fluoroanisole (10 g, 48.77 mmol) in toluene(100 mL) was added water (10 mL), cyclopropyl boronic acid (5.44 g, 63mmol), tricyclohexylphosphine (1.37 g, 4.87 mmol) and potassiumphosphate (36.3 g, 170 mmol). The reaction was degassed with nitrogenbefore the addition of Pd(OAc)₂ (547 mg, 2.44 mmol) followed by heatingto 100° C. for 3 hours. The reaction was cooled and partitioned betweenEtOAc and brine. The organic layer was collected, concentrated in vacuoand purified using silica gel column chromatography to afford the titlecompound as a colorless oil (9.7 g, quant).

¹H NMR (400 MHz, DMSO-d₆): δ ppm 0.65 (m, 2H), 0.92 (m, 2H), 1.88 (m,1H), 3.81 (s, 3H), 6.61 (m, 1H), 6.82 (m, 1H), 7.06 (m, 1H).

Preparation 156 4-Nitrophenyl{5-chloro-2-[methyl(methylsulfonyl)amino]benzyl}carbamate

To a solution ofN-[2-(aminomethyl)-4-chlorophenyl]-N-methylmethanesulfonamidehydrochloride (Preparation 211, 3.20 g, 11.39 mmol) and sodium carbonate(3.62 g, 34.18 mmol) in DCM (50 mL) at 0° C., was added4-nitrophenylchloroformate (2.52 g, 12.53 mmol) and the reaction wasstirred at room temperature for 18 hours. The reaction was concentratedin vacuo and the residue purified by silica gel column chromatographyeluting with 55-100% EtOAc in hexanes to afford the title compound as apale yellow solid (2.20 g, 46%). ¹H NMR (400 MHz, DMSO-d₆): δ ppm 3.08(s, 3H), 3.17 (s, 3H), 4.32 (br m, 1H), 4.52 (br m, 1H), 7.40-7.61 (m,5H), 8.25 (m, 2H).

The following Preparations (Preparations 157-183) were preparedaccording to the method described for Preparation 156 using theappropriate amine as described below, and taken directly on to the nextstep;

Preparation Number Name Data/SM 157 4-nitrophenyl {2-N-[2-(aminomethyl)phenyl]-N- [ethyl(ethylsulfonyl)amino]benzyl}carbamateethylethanesulfonamide hydrochloride (Preparation 184). 1584-nitrophenyl [2-(4- 2-(4-hydroxyphenyl)ethanamine.hydroxyphenyl)ethyl]carbamate 159 4-nitrophenyl {2-N-[2-(aminomethyl)phenyl]-N-[(ethylsulfonyl)(methyl)amino]benzyl}carbamate methylethanesulfonamidehydrochloride (Preparation 185). 160 4-nitrophenyl (2-2-methylpropylamine. methylpropyl)carbamate 161 4-nitrophenyl{5-fluoro-2- N-[2-(aminomethyl)-4-fluorophenyl]-N-[methyl(methylsulfonyl)amino] methylmethanesulfonamide benzyl}carbamatehydrochloride (Preparation 186). 162 4-nitrophenyl {2-fluoro-6-N-[2-(aminomethyl)-3-fluorophenyl]-N- [methyl(methylsulfonyl)amino]methylmethanesulfonamide benzyl}carbamate hydrochloride (Preparation187). 163 4-nitrophenyl {2- N-[2-(aminomethyl)phenyl]-N-[ethyl(methylsulfonyl)amino]benzyl}carbamate ethylmethanesulfonamidehydrochloride (Preparation 188). 164 4-nitrobenzyl1-cyclopentylmethanamine (cyclopentylmethyl)carbamate 165 4-nitrophenyl{5-methyl-2- N-[2-(aminomethyl)-4-methylphenyl]-N-[methyl(methylsulfonyl)amino] methylmethanesulfonamide benzyl}carbamatehydrochloride (Preparation 189). 166 4-nitrophenyl {2-[methyl-N-[2-(aminomethyl)phenyl]-N- (methylsulfonyl)amino]benzyl}methylmethanesulfonamide (WO2010/ carbamate 058846A1). 167 4-nitrophenyl{2- N-[2-(aminomethyl)phenyl]-N- [methyl(phenylsulfonyl)amino]methylbenzenesulfonamide benzyl}carbamate hydrochloride (Preparation190). 168 4-nitrophenyl (2-{4- N-[4-(2- [(phenylsulfonyl)amino]phenyl}aminoethyl)phenyl]benzenesulfonamide 172ulph)carbamate (Preparation210). 169 4-nitrophenyl {2- N-[2-(aminomethyl)-4-methoxyphenyl]-[bis(methylsulfonyl)amino]-5- N-(methylsulfonyl)methanesulfonamidemethoxybenzyl}carbamate hydrochloride (Preparation 191). 170 Racemic4-nitrophenyl (1-{2- Racemic N-[2-(1-aminoethyl)phenyl]-N-[methyl(methylsulfonyl)amino] methylmethanesulfonamidephenyl}ethyl)carbamate (Preparation 209). 171 4-nitrobenzyl (2-N-[2-(aminomethyl)phenyl]-N-[2- {(methylsulfonyl)[2-(tetrahydro-(tetrahydro-2H-pyran-2- 2H-pyran-2- yloxy)ethyl]methanesulfonamideyloxy)ethyl]amino}benzyl)carbamate (Preparation 216) 172 4-nitrophenyl{4-methoxy-2- N-[2-(aminomethyl)-5-methoxyphenyl]-[methyl(methylsulfonyl)amino] N-methylmethanesulfonamidebenzyl}carbamate hydrochloride (Preparation 192). 173 4-nitrophenyl(2-{[(3- N-[2-(aminomethyl)phenyl]-3-methoxy-methoxyphenyl)sulfonyl](methyl)amino}benzyl)carbamateN-methylbenzenesulfonamide hydrochloride (Preparation 193). 1744-nitrophenyl {2- N-[2-(aminomethyl)-4-methoxyphenyl]-[ethyl(methylsulfonyl)amino]-5- N-ethylmethanesulfonamidemethoxybenzyl}carbamate hydrochloride (Preparation 194). 1754-nitrophenyl {5-methoxy-2- N-[2-(aminomethyl)-4-methoxyphenyl]-[methyl(phenylsulfonyl)amino] N-methylbenzenesulfonamidebenzyl}carbamate hydrochloride (Preparation 195). 176 4-nitrophenyl {2-N-[2-(aminomethyl)-4-methoxyphenyl]- [ethyl(phenylsulfonyl)amino]-5-N-ethylbenzenesulfonamide methoxybenzyl}carbamate hydrochloride(Preparation 196). 177 4-nitrophenyl ({2-N-[3-(aminomethyl)pyridin-2-yl]-N- [methyl(methylsulfonyl)amino]methylmethanesulfonamide pyridin-3-yl}methyl)carbamate (Preparation 217)178 benzyl methyl[2-({[(4- Benzyl [2- nitrophenoxy)carbonyl]amino}(aminomethyl)phenyl]methylcarbamate methyl)phenyl]carbamatehydrochloride (Preparation 249). 179 4-nitrophenyl {2-N-[2-(aminomethyl)-4-fluorophenyl]-N- [ethyl(methylsulfonyl)amino]-5-ethylmethanesulfonamide fluorobenzyl}carbamate (Preparation 205). 1804-nitrophenyl {2- N-[2-(aminomethyl)-4-chlorophenyl]-N-[ethyl(methylsulfonyl)amino]-5- ethylmethanesulfonamidechlorobenzyl}carbamate (Preparation 206). 181 4-nitrobenzyl((5-methyl-2-(N- N-[3-(aminomethyl)-5-methylpyridin-2-methylmethylsulfonamido)pyridin- yl]-N-methylmethanesulfonamide3-yl)methyl)carbamate hydrochloride (Preparation 198). 182 4-nitrophenyl((2-(N- N-[3-(aminomethyl)-5-methylpyridin-2- ethylmethylsulfonamido)-5-yl]-N-ethylmethanesulfonamide methylpyridin-3- hydrochloride(Preparation 207). yl)methyl)carbamate 183 4-nitrophenyl {2-N-[2-(aminomethyl)-4-methylphenyl]-N- [ethyl(methylsulfonyl)amino]-5-ethylmethanesulfonamide methylbenzyl}carbamate hydrochloride(Preparation 200).

The following Preparations (Preparations 184-207) were preparedaccording to the methods described in the three steps below:

1) Preparation 236

2) Preparation 213

3) Preparation 211

using the appropriate alkyl halide as described below:

Preparation Number Name Data/SM 184 N-[2-(aminomethyl)- ¹H NMR (400 MHz,DMSO-d₆): δ ppm 3.06 (s, phenyl]-N- 3H), 3.22 (s, 3H), 4.09 (b s, 1H),4.21 (b s, 1H), ethylethanesulfonamide 7.47-7.52 (m, 2H), 7.62-7.63 (m,2H), 8.23 (b s, hydrochloride 1H). Using N-(2-cyanophenyl)-N-(ethylsulfonyl)ethanesulfonamide (Preparation 241) and ethyl iodide. 185N-[2- MS m/z 229 [M + H]⁺ (aminomethyl)phenyl]- ¹H NMR (400 MHz,DMSO-d₆): δ ppm 1.26 (t, N- 3H), 3.06-3.56 (br m, 4H), 4.03-4.19 (br m,2H), methylethanesulfonamide 7.42-7.49 (m, 2H), 7.60 (m, 1H), 7.68 (m,1H), hydrochloride 8.48 (br s, 3H). UsingN-(2-cyanophenyl)-N-(ethylsulfonyl) ethanesulfonamide (Preparation 241)and methyl iodide. 186 N-[2-(aminomethyl)- MS m/z 233 [M + H]⁺4-fluorophenyl]-N- ¹H NMR (400 MHz, DMSO-d₆): δ ppm 3.06 (s,methylmethanesulfonamide 3H), 3.56 (s, 3H), 4.02 (br s, 1H), 4.20 (br s,1H), hydrochloride 7.32-7.37 (m, 1H), 7.56-7.59 (m, 1H), 7.68-7.71 (m,1H), 8.49 (br s, 2H). Using N-(4-fluoro-2-cyanophenyl)-N-(methylsulfonyl)-methanesulfonamide (Preparation 239) and methyl iodide.187 N-[2-(aminomethyl)- MS m/z 233 [M + H]⁺ 3-fluorophenyl]-N- ¹H NMR(400 MHz, DMSO-d₆): δ ppm 3.06 (s, methylmethanesulfonamide 3H), 3.27(s, 3H), 4.05 (br s, 1H), 4.20 (br s, 1H), hydrochloride 7.36-7.41 (t,1H), 7.52-7.62 (m, 2H), 8.38 (br s, 2H). UsingN-(3-fluoro-2-cyanophenyl)-N- (methylsulfonyl)methanesulfonamide(Preparation 240) and methyl iodide. 188 N-[2- MS m/z 229 [M + H]⁺(aminomethyl)phenyl]- ¹H NMR (400 MHz, DMSO-d₆): δ ppm 1.26 (t, N- 3H),3.13 (m, 1H), 3.24 (s, 3H), 3.39 (m, 1H), ethylmethanesulfonamide 4.03(br s, 1H), 4.19 (br s, 1H), 7.44-7.49 (m, hydrochloride 2H), 7.59-7.70(m, 2H), 8.48 (br s, 2H). Using N-(2-cyanophenyl)-N-(methylsulfonyl)methanesulfonamide (Preparation 238) and ethyl iodide.189 N-[2-(aminomethyl)- MS m/z 229 [M + H]⁺ 4-methylphenyl]-N- ¹H NMR(400 MHz, DMSO-d₆): δ ppm 2.34 (s, methylmethanesulfonamide 3H), 3.03(s, 3H), 3.19 (s, 3H), 3.98 (br s, 1H), hydrochloride 4.17 (br s, 1H),7.29-7.31 (d, 1H), 7.47-7.51 (m, 2H), 8.33 (br s, 2H). UsingN-(4-methyl-2-cyanophenyl)-N- (methylsulfonyl)methanesulfonamide(Preparation 242) and methyl iodide. 190 N-[2-(aminomethyl)- MS m/z 277[M + H]⁺ phenyl]-N- ¹H NMR (400 MHz, DMSO-d₆): δ ppm 3.10 (s,methylbenzenesulfonamide 3H), 4.20 (br m, 1H), 4.40 (br m, 1H), 6.51 (m,hydrochloride 1H), 7.16 (m, 1H), 7.33 (m, 3H), 7.64 (m, 4H), 7.77 (m,1H). Using N-(2-cyanophenyl)-N- (phenylsulfonyl)benzenesulfonamide(Preparation 243) and methyl iodide. 191 N-[2-(aminomethyl)- ¹H NMR (400MHz, DMSO-d₆): δ ppm 3.05 (s, 4-methoxyphenyl]-N- 3H), 3.18 (s, 3H),3.80 (s, 3H), 3.99 (m, 1H), (methylsulfonyl)methanesulfonamide 4.18 (m,1H), 7.02 (dd, 1H), 7.26 (d, 1H), 7.54 (d, 1H), hydrochloride 8.43 (brs, 3H). Using N-(2-cyano-4-methoxyphenyl)-N-(methylsulfonyl)methanesulfonamide (Preparation 244). 192N-[2-(aminomethyl)- MS m/z 245 [M + H]⁺ 5-methoxyphenyl]-N- ¹H NMR (400MHz, DMSO-d₆): δ ppm 3.07 (s, methylmethane- 3H), 3.22 (s, 3H), 3.81 (s,3H), 3.93 (br m, 1H), sulfonamide 4.13 (br m, 1H), 7.07 (dd, 1H), 7.17(d, 1H), hydrochloride 7.58 (d, 1H), 8.24 (br s, 3H). UsingN-(2-cyano-5-methoxyphenyl)-N- methylmethanesulfonamide (Preparation224). 193 N-[2-(aminomethyl)- MS m/z 307 [M + H]⁺ phenyl]-3-methoxy- ¹HNMR (400 MHz, DMSO-d₆): δ ppm 3.37 (s, N- 3H), 3.78 (s, 3H), 4.11 (m,1H), 4.31 (m, 1H), methylbenzenesulfonamide 6.61 (m, 1H), 6.99 (m, 1H),7.17 (d, 1H), hydrochloride 7.28-7.35 (m, 2H), 7.42-7.46 (m, 1H), 7.56(t, 1H), 7.73 (m, 1H), 8.53 (br s, 3H). UsingN-(2-cyanophenyl)-3-methoxy-N- methylbenzenesulfonamide (Preparation225). 194 N-[2-(aminomethyl)- MS m/z 259 [M + H]⁺ 4-methoxyphenyl]-N- ¹HNMR (400 MHz, DMSO-d₆): δ ppm 0.99 (t, ethylmethane- 3H), 3.02 (3.46 (m,1H), 3.71 (m, 1H), 3.81 (s, sulfonamide 3H), 4.09 (m, 2H), 7.02 (dd,1H), 7.30 (d, 1H), hydrochloride 7.50 (d, 1H), 8.40 (br s, 3H).N-(2-cyano-4-methoxyphenyl)-N-(methylsulfonyl)- methanesulfonamide(Preparation 244) and ethyl iodide. 195 N-[2-(aminomethyl)- MS m/z 307[M + H]⁺ 4-methoxyphenyl]-N- ¹H NMR (400 MHz, DMSO-d₆): δ ppm 3.11 (s,methylbenzenesulfonamide 3H), 3.54 (s, 3H), 4.06 (m, 1H), 4.30 (m, 1H),hydrochloride 6.45 (d, 1H), 6.82 (m, 1H), 7.30 (d, 1H), 7.58-7.75 (m,4H), 7.77 (m, 1H), 8.41 (br s, 3H). N-(4-methoxy-2-cyanophenyl)-N-(phenylsulfonyl)benzenesulfonamide (Preparation 246) and methyl iodide.196 N-[2-(aminomethyl)- MS m/z 321 [M + H]⁺ 4-methoxyphenyl]-N- ¹H NMR(400 MHz, DMSO-d₆): δ ppm 0.96 (t, ethylbenzene- 3H), 3.20 (m, 1H), 3.78(s, 3H), 3.86 (m, 1H), sulfonamide 4.15 (m, 2H), 6.47 (d, 1H), 6.85 (m,1H), 7.31 (s, hydrochloride 1H), 7.61 (m, 4H), 7.76 (m, 1H), 8.40 (br s,3H). N-(4-methoxy-2-cyanophenyl)-N- (phenylsulfonyl)benzenesulfonamide(Preparation 246) and ethyl iodide. 197 N-(3- MS m/z 216 [M + H]⁺(aminomethyl)pyridin- Using N-(3-cyanopyridin-4- 4-yl)-N-yl)methanesulfonamide (Preparation 248) and methylmethanesulfonamidemethyl iodide. 198 N-[3-(aminomethyl)- ¹H NMR (400 MHz, DMSO-d₆): δ ppm2.36 (s, 5-methylpyridin-2-yl]- 3H), 3.09 (s, 3H), 3.18 (s, 3H), 7.90(d, 1H), N- 8.26 (br s, 3H), 8.39 (d, 1H). methylmethanesulfonamide MSm/z 230 [M + H]⁺ hydrochloride Using N-(3-cyano-5-methylpyridin-2-yl)-N-(methylsulfonyl)methanesulfonamide (Preparation 245) and methyl iodide.199 1-[2-(aminomethyl)- MS m/z 201 [M + H]⁺ phenyl]methanesulfonamide ¹HNMR (400 MHz, DMSO-d₆): δ ppm 4.18 (br m, hydrochloride 2H), 4.48 (s,2H), 7.00 (s, 2H), 7.43 (m, 3H), 7.53 (m, 1H), 8.23 (br s, 3H). UsingSteps 2 and 3 only with (2- cyanophenyl)methanesulfonamide. 200N-[2-(aminomethyl)- MS m/z 243 [M + H]⁺ 4-methylphenyl]-N- ¹H NMR (400MHz, DMSO-d₆): δ ppm 0.98 (t, ethylmethaneulfonamide 3H), 2.50 (s, 3H),3.03 (s, 3H), 3.49 (m, 1H), hydrochloride 3.70 (m, 1H), 4.09 (m, 2H),7.29 (m, 1H), 7.45 (d, 1H), 7.51 (s, 1H), 8.42 (br s, 3H). MS m/z 243[M + H]⁺ Using N-(4-methyl-2-cyanophenyl)-N-(methylsulfonyl)-methanesulfonamide (Preparation 242) and ethyl iodide.201 N-[3-(aminomethyl)- MS m/z 264 [M + H]⁺ 5-chloropyridin-2-yl]- ¹HNMR (400 MHz, DMSO-d₆): δ ppm 0.99 (t, N-ethylmethane- 3H), 3.07 (s,3H), 3.70 (q, 2H), 4.17 (m, 2H), sulfonamide 8.31 (s, 1H), 8.44 (br s,3H), 8.67 (s, 1H). hydrochloride Using steps 2 and 3 only withN-(5-chloro-3- cyanopyridin-2-yl)-N-ethylmethanesulfonamide (Preparation232). 202 N-[3-(aminomethyl)- MS m/z 250 [M + H] 5-chloropyridin-2-yl]-¹H NMR (400 MHz, DMSO-d₆): δ ppm 2.98 (s, N- 3H), 3.29 (s, 3H), 4.39 (m,2H), 8.46 (s, 1H), methylmethanesulfonamide 8.57 (m, 1H), 8.70 (br s,3H). hydrochloride Using steps 2 and 3 only with N-(5-chloro-3-cyanopyridin-2-yl)-N-methylmethanesulfonamide (Preparation 233). 203N-[3-(aminomethyl)- ¹H NMR (400 MHz, DMSO-d₆): δ ppm 3.07 (s,5-fluoropyridin-2-yl]- 3H), 3.19 (s, 3H), 4.18 (br s, 2H), 8.10 (dd,1H), N- 8.40 (br s, 3H), 8.60 (d, 1H). methylmethanesulfonamide Usingsteps 2 and 3 only with N-(5-fluoro-3- hydrochloridecyanopyridin-2-yl)-N-methylmethanesulfonamide (Preparation 231). 204N-[3-(aminomethyl)- MS m/z 250 [M + H] 5-fluoropyridin-2-yl]- Usingsteps 2 and 3 only with N-(5-fluoro-3- N-ethylmethane-cyanopyridin-2-yl)-N-ethylmethanesulfonamide sulfonamide (Preparation235). Taken on directly to the next hydrochloride step. 205N-[2-(aminomethyl)- MS m/z 247 [M + H] 4-fluorophenyl]-N- ¹H NMR (400MHz, DMSO-d₆): δ ppm 0.98 (t, ethylmethanesulfonamide 3H), 3.07 (s, 3H),3.48 (m, 1H), 3.64 (m, 1H), 3.71-3.83 (q, 2H), 7.13 (m, 1H), 7.44 (m,2H). Using N-(4-fluoro-2-cyanophenyl)-N-(methylsulfonyl)-methanesulfonamide (Preparation 239), ethyl iodide andwashing with saturated aqueous sodium bicarbonate solution. 206N-[2-(aminomethyl)- MS m/z 263 [M + H] 4-chlorophenyl]-N- ¹H NMR (400MHz, DMSO-d₆): δ ppm 1.00 (t, ethylmethanesulfonamide 3H), 3.55 (m, 1H),3.75 (m, 1H), 4.03-4.20 (m, hydrochloride 2H), 7.55 (dd, 1H), 7.62 (m,1H), 7.83 (d, 1H), 8.54 (br s, 3H). Using N-(4-chloro-2-cyanophenyl)-N-methylmethanesulfonamide (Preparation 237). 207 N-[3-(aminomethyl)- MSm/z 244 [M + H] 5-methylpyridin-2-yl]- ¹H NMR (400 MHz, DMSO-d₆): δ ppm0.95 (t, N- 3H), 2.49 (s, 3H), 3.59 (s, 3H), 3.65 (q, 2H),ethylmethanesulfonamide 4.10 (m, 2H), 8.07 (d, 1H), 8.40 (d, 1H), 8.71(br s, hydrochloride 3H). Using N-(3-cyano-5-methylpyridin-2-yl)-N-(methylsulfonyl)methanesulfonamide (Preparation 245) and ethyl iodide.

Preparation 208 tert-Butyl2-(N-methyl-2-oxooxazolidine-3-sulfonamido)benzylcarbamate hydrochloride

To a suspension of tert-butyl(2-((2-oxooxazolidine)-3-sulfonamido)benzyl)carbamate (Preparation 251,2.5 g, 6.73 mmol) and anhydrous potassium carbonate (2.32 g, 16.82 mmol)in acetone (300 mL) was added methyl iodide (2.39 g, 16.83 mmol) and thereaction heated to reflux for 18 hours. The reaction was cooled andconcentrated in vacuo. The residue was partitioned between water andDCM, the organic layer was collected, washed with brine and concentratedin vacuo. The residue was purified using silica gel columnchromatography eluting with 35% EtOAc in hexanes before being treatedwith 4M HCl in dioxane (7 mL) and stirring at room temperature for 18hours. The reaction was concentrated in vacuo and triturated withether/pentane to afford the title compound as the hydrochloride salt(1.60 g, 68% over 2 steps). ¹H NMR (400 MHz, DMSO-d₆): δ ppm 3.36 (s,3H), 3.56 (m, 1H), 3.98 (m, 1H), 4.08 (m, 1H), 4.19 (m, 1H), 4.44 (m,2H), 7.52-7.68 (m, 4H), 8.36 (br s, 3H). MS m/z 285 [M+H]⁺

Preparation 209 RacemicN-[2-(1-Aminoethyl)phenyl]-N-methylmethanesulfonamide

To a solution of N-(2-acetylphenyl)-N-methylmethanesulfonamide(Preparation 246, 10 g, 43.99 mmol) in EtOH (150 mL) was addedtriethylamine (7.93 mL, 57 mmol) and hydroxylamine hydrochloride (3.98g, 57 mmol) and the reaction was heated to 80° C. for 18 hours. Thereaction was cooled, diluted with EtOAc, washed with brine, dried oversodium sulfate and concentrated in vacuo. The residue was dissolved inMeOH (50 mL) and ammonium formate (2.15 g, 34 mmol) and activated zincdust (2.25 g, 34 mmol) were added. The reaction was heated to reflux for18 hours. The reaction was filtered through celite and concentrated invacuo. The residue was purified using silica gel column chromatographyeluting with 12% MeOH in DCM to afford the title compound as a colorlessoil (1.2 g, 77%). ¹H NMR (400 MHz, DMSO-d₆): δ ppm 1.48 (d, 3H), 3.16(s, 3H), 3.22 (s, 3H), 4.76 (m, 1H), 7.40-7.80 (m, 4H), 8.32 (s, 1H). MSm/z 229 [M+H]⁺

Preparation 210 N-[4-(2-Aminoethyl)phenyl]benzenesulfonamide

To a solution of 2-(2-aminoethyl)aniline (30 g, 220 mmol) in DCM (700mL) at 0° C. was added triethylamine (36.8 mL, 264 mmol) followed bytert-butyldicarbonate (52.9 g, 242 mmol) and the reaction was allowed towarm to room temperature stirring for 2 hours. The reaction was added towater (500 mL), the organic layer collected, washed with brine, driedover sodium sulfate and concentrated in vacuo to afford a yellow oil.The oil was dissolved in DCM (400 mL) and pyridine (20 mL), andbenzenesulfonyl chloride (26.1 mL, 203 mmol) was added. The reaction wasstirred at room temperature for 48 hours. Further benzenesulfonylchloride (6.51 mL, 0.3 eq) was added and the reaction continued for 24hours. The reaction was washed with 1M aqueous HCl solution (500 mL),concentrated aqueous ammonia solution (400 mL), brine (500 mL), driedover sodium sulfate and concentrated in vacuo. The residue wasrecrystallised from EtOAc/Ether to afford a white solid. The solid wasdissolved in dioxane (200 mL), 4M HCl in dioxane (282 mL) was added andthe reaction was stirred at room temperature for 18 hours. The reactionwas concentrated in vacuo and the residue suspended in hot MeOH (150mL). 7M ammonia in MeOH (150 mL) was added and the solution cooled. Theresulting precipitate was collected and purified further using silicagel column chromatography eluting with 0.4% NH₃ in 10-15% MeOH in DCM toafford the title compound as a yellow solid (16.8 g, 26% over threesteps).

¹H NMR (400 MHz, DMSO-d₆): δ ppm 2.64 (t, 2H), 2.82 (t, 2H), 6.95-7.05(m, 4H), 7.50-7.60 (m, 3H), 7.53 (m, 2H). MS m/z 275 [M−H]⁻

Preparation 211N-[2-(Aminomethyl)-4-chlorophenyl]-N-methylmethanesulfonamidehydrochloride

To a solution of tert-butyl{5-chloro-2-[methyl(methylsulfonyl)-amino]benzyl}carbamate (Preparation213, 8.2 g, 23 mmol) in MeOH (100 mL) was added 4M HCl in dioxane (100mL) at 0° C. and the reaction was stirred at room temperature for 5hours. The reaction was concentrated in vacuo and triturated with a 1:1mixture of MeCN:ether to afford the title compound as the hydrochloridesalt (8.00 g, 100%). ¹H NMR (400 MHz, DMSO-d₆): δ ppm 3.07 (s, 3H), 3.20(s, 3H), 4.05 (br m, 1H), 4.20 (br m, 1H), 7.58 (m, 1H), 7.66 (m, 1H),7.73 (m, 1H), 8.32 (br s, 3H). MS m/z 249 [M+H]

Preparation 212N-[2-(Aminomethyl)-4-methoxyphenyl]-N-methylpyridine-3-sulfonamidedihydrochloride

The title compound was prepared according to the method described forPreparation 211 using tert-butyl{5-methoxy-2-[methyl(pyridin-3-ylsulfonyl)amino]benzyl}carbamate(Preparation 214). MS m/z 308 [M+H]⁺

Preparation 213 tert-Butyl{5-chloro-2-[methyl(methylsulfonyl)amino]benzyl}carbamate

To a solution of N-(4-chloro-2-cyanophenyl)-N-methylmethanesulfonamide(Preparation 236, 6.20 g, 25.40 mmol) in MeOH (150 mL) was addeddi-tert-butyl dicarbonate (11.71 mL, 50.82 mmol) and NiCl₂.6H₂O (1.20 g,5.08 mmol). The reaction was cooled to 0° C. and NaBH₄ (9.61 g, 254mmol) was added portion-wise. The reaction was stirred at roomtemperature for 6 hours before being quenched by the addition ofdiethylenetriamine with stirring for 30 minutes. The reaction wasconcentrated in vacuo and partitioned between EtOAc and saturatedaqueous sodium bicarbonate. The organic layer was collected, dried oversodium sulfate and concentrated in vacuo. The residue was purified bysilica gel column chromatography to afford the title compound (8.20 g,93%). 1H NMR (400 MHz,

DMSO-d₆): 3.06 (s, 3H), 3.21 (s, 3H), 4.01-4.19 (m, 2H), 7.54-7.57 (q,1H), 7.65-7.68 (d, 1H), 7.82-7.83 (d, 1H) MS m/z 349 [M+H]⁺ and 249[M-Boc+H]⁺

Preparation 214 tert-Butyl{5-methoxy-2-[methyl(pyridin-3-ylsulfonyl)amino]benzyl}carbamate

To a solution of tert-butyl [5-methoxy-2-(methylamino)benzyl]carbamate(Preparation 215, 3.8 g, 10 mmol) in THF (20 mL) was added NaH (373 mg,15 mmol) at 0° C. and the reaction was stirred for 15 minutes before theaddition of pyridine-3-sulfonyl chloride (1.36 mL, 11 mmol) dropwise.The reaction was stirred at room temperature for 18 hours before beingquenched with water and extracted into EtOAc. The organic layer wascollected, washed with water, brine, dried over sodium sulfate andconcentrated in vacuo. The residue was purified using silica gel columnchromatography eluting with 55% EtOAc in hexanes to afford the titlecompound (3.3 g, 78%). MS m/z 407 [M−H]−

Preparation 215 tert-Butyl [5-methoxy-2-(methylamino)benzyl]carbamate

The title compound was prepared according to the method described forPreparation 213 using 5-methoxy-2-(methylamino)benzonitrile (Preparation250). ¹H NMR (400 MHz, DMSO-d₆): δ ppm 1.37 (s, 9H), 2.66 (d, 3H), 3.63(s, 3H), 3.95 (m, 2H), 4.77 (br s, 1H), 6.45 (d, 1H), 6.63 (br s, 1H),6.69 (dd, 1H), 7.23 (br t, 1H). MS m/z 267 [M+H]⁺

Preparation 216N-[2-(Aminomethyl)phenyl]-N-[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]methanesulfonamide

To a solution ofN-(2-cyanophenyl)-N-[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]methanesulfonamide(Preparation 222, 8 g, 25 mmol) in MeOH (100 mL) was added NiCl₂.6H₂O(1.17 g, 5 mmol) followed by sodium borohydride (6.53 g, 172 mmol) at 0°C. The reaction was stirred at room temperature for 4 hours before beingquenched by the addition of diethylenetetramine. The reaction wasconcentrated in vacuo and purified using silica gel columnchromatography eluting with 10% MeOH in DCM to afford the title compound(4.9 g, 60%). Taken on directly to the next step.

Preparation 217N-[3-(Aminomethyl)pyridin-2-yl]-N-methylmethanesulfonamide

To a solution of N-(3-cyanopyridin-2-yl)-N-methylmethanesulfonamide(Preparation 230, 10 g, 47 mmol) in methanolic ammonia (100 mL) wasadded Raney Nickel (2 g) and the reaction was hydrogenated at 40 psi atroom temperature for 18 hours. The reaction was filtered through celite,concentrated in vacuo and purified using silica gel columnchromatography eluting with 10% MeOH in DCM to afford the title compound(7.5 g, 74%). ¹H NMR (400 MHz, DMSO-d₆): δ ppm 3.13 (s, 6H), 3.82 (br s,2H), 7.44 (m, 1H), 8.03 (m, 1H), 8.37 (m, 1H).

Preparation 218N-[3-(Aminomethyl)pyridin-2-yl]-N-ethylmethanesulfonamide

The title compound was prepared according to the method described forPreparation 217 using N-(3-cyanopyridin-2-yl)-N-methylmethanesulfonamide(Preparation 234). ¹H NMR (400 MHz, DMSO-d₆): δ ppm 0.94 (t, 3H), 3.06(s, 3H), 3.63 (q, 2H), 3.86 (br s, 2H), 7.46 (m, 1H), 8.06 (m, 1H), 8.41(m, 1H). MS m/z 230 [M+H]

Preparation 219N-[3-(Aminomethyl)pyrazin-2-yl]-N-methylbenzenesulfonamide

A solution of N-(3-cyanopyrazin-2-yl)-N-methylbenzenesulfonamide(Preparation 228, 7.2 g, 32 mmol) in AcOH (100 mL) was purged undernitrogen for 15 minutes followed by the addition of 10% Pd—C (1.4 g) andhydrogenated under at 40 psi hydrogen in a Parr-shaker for 18 hours. Thereaction was filtered through celite, concentrated in vacuo, neutralizedwith 1N NaOH and extracted with DCM. The organic layer was collected,dried over sodium sulfate, concentrated in vacuo and purified by silicagel column chromatography eluting with 10% MeOH in DCM to afford thetitle compound as a yellow solid (4.1 g, 46%). ¹H NMR (400 MHz,DMSO-d₆): δ ppm 3.06 (s, 3H), 4.04 (s, 2H), 7.17 (m, 4H), 7.33 (m, 1H),8.34 (d, 1H), 8.64 (d, 1H). MS m/z 279 [M+H]⁺

Preparation 220 N-[2-(Aminomethyl)phenyl]-N-methylpyridine-3-sulfonamidehydrochloride

To a solution of tert-butyl{2-[(pyridin-3-ylsulfonyl)amino]benzyl}carbamate (Preparation 227, 4.57g, 12 mmol) in acetone (100 mL) was added potassium carbonate (5.20 g,38 mmol) followed by methyl iodide (1.56 mL, 25 mmol). The reaction washeated to reflux for 2 hours. The reaction was evaporated to dryness andpartitioned between water & ethyl acetate. The organic phase was washedwith brine, dried over sodium sulfate, evaporated and purified by silicagel column chromatography eluting with 52% EtOAc in hexanes. The residuewas dissolved in MeOH (25 mL) and 4M HCl in dioxane (25 mL) was addedwith stirring at room temperature for 4 hours. The reaction wasconcentrated in vacuo and triturated with MeCN-ether to afford the titlecompound as the hydrochloride salt (4.2 g, 100%). ¹H NMR (400 MHz,DMSO-d₆): δ ppm 3.19 (s, 3H), 4.14 (m, 1H), 4.32 (m, 1H), 6.65 (d, 1H),7.31 (t, 1H), 7.47 (t, 1H), 7.67-7.72 (m, 2H), 7.99 (m, 1H), 8.36 (br s,3H), 8.71 (m, 1H), 8.95 (m, 1H),

Preparation 221N-[3-(Aminomethyl)pyrazin-2-yl]-N-ethylmethanesulfonamide

The title compound was prepared according to the method described forPreparation 219 using N-(3-cyanopyrazin-2-yl)-N-ethylmethanesulfonamide(Preparation 229). ¹H NMR (400 MHz, DMSO-d₆): δ ppm 1.00 (t, 3H), 1.86(br s, 2H), 3.13 (s, 3H), 3.68 (q, 2H), 3.95 (s, 2H). MS m/z 231 [M+H]⁺

Preparation 222N-(2-Cyanophenyl)-N-[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]methanesulfonamide

To a suspension of N-(2-cyanophenyl)methanesulfonamide (Preparation 223,7 g, 25 mmol) and polymer bound triphenylphosphine (14 g, 53 mmol) inanhydrous THF (100 mL) was added DEAD (8.42 mL, 53 mmol) followed by2-(tetrahydro-pyran-2-yloxy)ethanol (7.82 g, 146 mmol) drop-wise at 0°C. The reaction was stirred at room temperature for 5 hours beforefiltering through celite. The filtrate was concentrated in vacuo andpurified using silica gel column chromatography eluting with 30-35%EtOAc in hexanes to afford the title compound (8 g, 69%). ¹H NMR (400MHz, MeOD): δ ppm 1.42-1.62 (m, 6H), 3.14 (s, 3H), 3.40-3.55 (m, 2H),3.70-4.00 (m, 5H), 7.53 (m, 1H), 7.69 (m, 1H), 7.72-7.81 (m, 2H).

Preparation 223 N-(2-Cyanophenyl)-N-methylmethanesulfonamide

To a solution of N-(2-cyanophenyl)-N-(methylsulfonyl)methanesulfonamide(Preparation 238, 300 g, 1.09 mol) in THF (2 L) was added 40% aqueoussodium hydroxide (2 L), benzyl triethylammonium chloride (24.91 g, 0.100mol), and iodomethane (81.68 mL, 1.31 mol.) The reaction was stirred atroom temperature for 18 hours. The reaction was diluted with EtOAc andpartitioned with brine. The organic layer was collected, dried oversodium sulfate and concentrated in vacuo. The residue was triturated inpentane-ether to afford the title compound (208 g, 90%). ¹H NMR (400MHz, CDCl₃): δ ppm 3.11 (s, 3H), 3.38 (s, 3H), 7.43-7.47 (t, 1H),7.52-7.55 (m, 1H), 7.63-7.71 (m, 2H); MS m/z 211[M−H]⁻

Preparation 224 N-(2-Cyano-5-methoxyphenyl)-N-methylmethanesulfonamide

To a stirred solution of 4-methoxy-2-(methylamino)benzonitrile(Preparation 226, 11 g, 68 mmol) in THF at −78° C., 1M LiHMDS in THF(108.5 mL) was added drop wise. The solution was stirred for 30 minutesfollowed by the addition of methanesulfonyl chloride (7.92 mL, 102mmol). The reaction was stirred for 1 hour before quenching withsaturated aqueous ammonium chloride solution and extracting into EtOAc.The organic layer was collected, dried over sodium sulfate andconcentrated in vacuo. The residue was purified by silica gel columnchromatography eluting with 40% EtOAc in hexanes to afford the titlecompound as a white solid (12 g, 73%). ¹H NMR (400 MHz, DMSO-d₆): δ ppm3.13 (s, 3H), 3.26 (s, 3H), 3.88 (s, 3H), 7.11 (dd, 1H), 7.28 (d, 1H),7.83 (d, 1H).

Preparation 225 N-(2-Cyanophenyl)-3-methoxy-N-methylbenzenesulfonamide

The title compound was prepared according to the method described forPreparation 224 using 2-(methylamino)benzonitrile and3-methoxybenzenesulfonyl chloride. Taken on directly to the next step.MS m/z 303 [M+H]⁺

Preparation 226 4-Methoxy-2-(methylamino)benzonitrile

To a solution of 2-fluoro-4-methoxybenzonitrile (1 g, 6.61 mmol) in MeCN(10 mL) was added 40% aqueous methylamine (20 mL) and the reactionheated to 60° C. in a sealed tube. The reaction was cooled, concentratedin vacuo and purified using silica gel column chromatography elutingwith 60% EtOAc in hexanes to afford the title compound as a white solid(600 mg, 56%). ¹H NMR (400 MHz, DMSO-d₆): δ ppm 2.76 (d, 3H), 3.78 (s,3H), 6.12 (m, 2H), 6.22 (m, 1H), 7.37 (m, 1H). MS m/z 163 [M+H]⁺

Preparation 227 tert-Butyl{2-[(pyridin-3-ylsulfonyl)amino]benzyl}carbamate

To a solution of (2-amino-benzyl)-carbamic acid tert butyl ester (3.2 g,14 mmol) in pyridine (25 mL) was added pyridine-3-sulfonylchloride (1.75mL, 14 mmol) at 0° C. The reaction was stirred at room temperature for 4hours before concentrating in vacuo. The residue was partitioned betweenEtOAc and water, the organic layer was collected, dried over sodiumsulfate and concentrated in vacuo. The residue was purified using silicagel column chromatography eluting with 65% EtOAc in hexanes to affordthe title compound (4.5 g, 87%). ¹H NMR (400 MHz, DMSO-d₆): δ ppm 1.38(s, 9H), 4.07 (m, 2H), 6.80 (d, 1H), 7.13 (m, 1H), 7.21 (m, 2H), 7.32(m, 1H), 7.62 (m, 1H), 8.05 (m, 1H), 8.78-8.83 (m, 2H), 9.92 (s, 1H). MSm/z 364 [M+H]⁺

Preparation 228 N-(3-Cyanopyrazin-2-yl)-N-methylbenzenesulfonamide

To a solution of 2-chloro-3-cyanopyrazine (5 g, 35.94 mmol) and Cs₂CO₃(16.27 g, 50 mmol) in acetonitrile (75 mL) was addedN-methylbenzenesulfonamide (7.37 g, 43 mmol) and the reaction heated to80° C. for 3 hours. The reaction mixture was concentrated in vacuo andthe residue partitioned between water and EtOAc. The organic layer wascollected, dried, concentrated in vacuo and purified by silica gelcolumn chromatography eluting with 50% EtOAc in hexanes to afford thetitle compound (7.2 g, 73%). ¹H NMR (400 MHz, DMSO-d₆): δ ppm 3.12 (s,3H), 7.64 (m, 4H), 7.76 (m, 1H), 8.80 (d, 1H), 8.85 (d, 1H).

Preparation 229 N-(3-Cyanopyrazin-2-yl)-N-ethylmethanesufonamide

The title compound was prepared according to the method described forPreparation 228 using N-ethylmethanesulfonamide. ¹H NMR (400 MHz,DMSO-d₆): δ ppm 1.09 (t, 3H), 3.20 (s, 3H), 3.83 (q, 2H), 8.89 (d, 1H),8.97 (d, 1H).

Preparation 230 N-(3-Cyanopyridin-2-yl)-N-methylmethanesulfonamide

To a solution of 2-chloronicotinonitrile (10 g, 71.9 mmol) in MeCN (200mL) was added cesium carbonate (32.5 g, 99 mmol) followed byN-methylmethanesulfonamide (9.42 g, 86 mmol) and the reaction was heatedto 80° C. for 3 hours. The reaction was cooled, concentrated in vacuoand partitioned between EtOAc and water. The organic layer wascollected, dried over sodium sulfate and concentrated in vacuo. Theresidue was purified using silica gel column chromatography eluting with50% EtOAc in hexanes to afford the title compound (12.9 g, 85%). ¹H NMR(400 MHz, DMSO-d₆): δ ppm 3.21 (s, 3H), 3.28 (s, 3H), 7.62 (m, 1H), 8.45(d, 1H), 8.77 (d, 1H). MS m/z 212 [M+H]⁺

The following Preparations (Preparations 231-235) were preparedaccording to the method described for Preparation 230 using theappropriate chloropyridine and sulfonamide as described below, and takendirectly on to the next step:

Preparation Number Name Data/SM 231 N-(5-fluoro-3- MS m/z 230 [M + H]⁺cyanopyridin-2-yl)-N- Using N-methylmethanesulfonamide and 2-methylmethanesulfonamide chloro-5-fluoronicotinonitrile. 232N-(5-chloro-3- MS m/z 260 [M + H]⁺ cyanopyridin-2-yl)-N- ¹H NMR (400MHz, DMSO-d₆): δ ppm 1.17 (t, ethylmethanesulfonamide 3H), 3.10 (s, 3H),3.87 (q, 2H), 8.02 (s, 1H), 8.62 (s, 1H). UsingN-ethylmethanesulfonamide and 2,5- dichloronictinonitrile. 233N-(5-chloro-3- MS m/z 246 [M + H]⁺ cyanopyridin-2-yl)-N- ¹H NMR (400MHz, DMSO-d₆): δ ppm 3.21 (s, methylmethanesulfonamide 3H), 3.27 (s,3H), 8.73 (d, 1H), 8.86 (d, 1H). Using N-methylmethanesulfonamide and2,5- dichloronictinonitrile. 234 N-(3-cyanopyridin-2- MS m/z 226 [M +H]⁺ yl)-N- ¹H NMR (400 MHz, DMSO-d₆): δ ppm 1.05 (t,ethylmethanesulfonamide 3H), 3.17 (s, 3H), 3.77 (q, 2H), 7.67 (m, 1H),8.49 (m, 1H), 8.84 (m, 1H). Using 2-chloronicotinonitrile and N-ethylmethanesulfonamide. 235 N-(5-fluoro-3- MS m/z 244 [M + H]⁺cyanopyridin-2-yl)-N- Using N-ethylmethanesulfonamide and 2-ethylmethanesulfonamide chloro-5-fluoronicotinonitrile.

Preparation 236 N-(4-Chloro-2-cyanophenyl)-N-methylmethanesulfonamide

A solution ofN-(4-chloro-2-cyanophenyl)-N-(methylsulfonyl)methanesulfonamide(Preparation 237, 8.00 g, 25.91 mmol) in THF (100 mL) and 40% aqueousNaOH solution (100 mL) was cooled to 0° C. Benzyltriethylammoniumchloride (0.59 g, 2.591 mmol) and Mel (5.64 mL, 90.68 mmol) were addedand the reaction was stirred for 18 hours. The reaction was partitionedbetween EtOAc and water and concentrated in vacuo. The residue waspurified by silica gel column chromatography eluting with 30% EtOAc inhexanes to afford the title compound as a yellow solid (6.20 g, 97%). ¹HNMR (400 MHz, DMSO-d₆): δ ppm 3.14 (s, 3H), 3.26 (s, 3H), 7.78 (d, 1H),7.88 (dd, 1H), 8.13 (d, 1H).

Preparation 237N-(4-Chloro-2-cyanophenyl)-N-(methylsulfonyl)methanesulfonamide

To a solution of 2-amino-5-chloro-benzonitrile (5.00 g, 32.77 mmol) inpyridine (100 mL) at 0° C. was added methanesulphonylchloride (10.21 mL,131.07 mmol) and the reaction stirred at room temperature for 18 hours.The reaction was concentrated in vacuo and partitioned between 2N HCland EtOAc. The organic layer was collected, washed with brine, driedover sodium sulfate and concentrated in vacuo. The residue wastriturated with 1:1 acetonitrile:ether to afford the title compound(8.00 g, 79%).

¹H NMR (400 MHz, DMSO-d₆): δ ppm 3.61 (s, 6H), 7.90 (d, 1H), 7.98 (dd,1H), 8.31 (d, 1H).

The following Preparations (Preparations 238-246) were preparedaccording to the method described for Preparation 237 using theappropriate aniline as described below:

Preparation Number Name Data/SM 238 N-(2-cyanophenyl)-N- ¹H NMR (400MHz, DMSO-d₆): δ ppm 1.10 (t, (methylsulfonyl)methanesulfonamide 3H),3.12 (s, 3H), 3.67-3.73 (q, 2H), 7.59 (t, 1H), 7.73-7.75 (d, 1H), 7.82(t, 1H), 7.93 (d, 1H). Using 2-aminobenzonitrile. 239N-(4-fluoro-2-cyano- ¹H NMR (400 MHz, DMSO-d₆): δ ppm 3.61 (s,phenyl)-N-(methyl- 6H), 7.70-7.80 (m, 1H), 7.93-7.96 (m, 1H),sulfonyl)methanesulfonamide 8.11-8.14 (m, 1H). Using2-amino-5-fluorobenzonitrile. 240 N-(3-fluoro-2-cyano- ¹H NMR (400 MHz,DMSO-d₆): δ ppm 3.10 (s, phenyl)-N- 3H), 3.20 (s, 3H), 7.54-7.58 (m,1H), (methylsulfonyl)- 7.63-7.65 (m, 1H), 7.83-7.89 (m, 1H).methanesulfonamide Using 2-amino-6-fluorobenzonitrile. 241N-(2-cyanophenyl)-N- Taken on directly to the next step as crude.(ethylsulfonyl)ethanesulfon- Using 2-aminobenzonitrile. amide 242N-(4-methyl-2- ¹H NMR (400 MHz, DMSO-d₆): δ ppm 2.44 (s, cyanophenyl)-N-3H), 3.50 (s, 6H), 7.35-7.37 (d, 1H), (methylsulfonyl)- 7.48-7.50 (d,1H), 7.59 (s, 1H). methanesulfonamide Using2-amino-5-methylbenzonitrile. 243 N-(2-cyanophenyl)-N- MS m/z 399 [M +H]⁺ (phenylsulfonyl)benzene- ¹H NMR (400 MHz, DMSO-d₆): δ ppm 7.18 (m,sulfonamide 1H), 7.65-7.88 (m, 12H), 8.02 (m, 1H). Using2-aminobenzonitrile and benzenesulfonyl chloride. 244N-(2-cyano-4-methoxyphenyl)- ¹H NMR (400 MHz, DMSO-d₆): δ ppm 3.57 (s,N- 6H), 3.87 (s, 3H), 7.37 (dd, 1H), 7.65 (d, 1H),(methylsulfonyl)methane- 7.75 (d, 1H). sulfonamide Using2-amino-4-methoxybenzonitrile and methanesulfonyl chloride. 245N-(3-cyano-5-methyl- Taken directly on to the next step.pyridin-2-yl)-N- Using 2-amino-5-methylpyridine-3-carbonitrile(methylsulfonyl)methane- and methanesulfonyl chloride. sulfonamide 246N-(4-methoxy-2- Taken directly on to the next step. cyanophenyl)-N-Using 2-amino-5-methylpyridine-3-carbonitrile (phenylsulfonyl)benzene-and methanesulfonyl chloride. sulfonamide

Preparation 247 N-(2-Acetylphenyl)-N-methylmethanesulfonamide

To a solution of N-[2-(aminomethyl)phenyl]-N-methylmethanesulfonamide(Preparation 252, 10.5 g, 49 mmol) in acetone (250 mL) was addedpotassium carbonate (13.59 g, 98.47 mmol) and methyl iodide (6.13 mL,98.47 mmol) at 0° C. followed by heating to 60° C. for 4 hours. Thereaction was cooled and concentrated in vacuo. The residue waspartitioned between EtOAc and water, the organic layer was collected,washed with brine, dried and concentrated in vacuo. The residue waspurified using silica gel column chromatography eluting with 40% EtOAcin hexanes to afford the title compound (10 g, 89%). ¹H NMR (400 MHz,DMSO-d₆): δ ppm 2.54 (s, 3H), 2.97 (s, 3H), 3.29 (s, 3H), 7.46 (m, 1H),7.60-7.64 (m, 3H). MS m/z 228 [M+H]⁺

Preparation 248 N-[3-(Aminomethyl)pyridin-4-yl]methanesulfonamide

The title compound was prepared according to the method described forPreparation 247 using 3-cyano-4-aminopyridine. ¹H NMR (400 MHz,DMSO-d₆): δ ppm 2.92 (s, 3H), 7.31 (d, 1H), 7.99 (d, 1H), 8.66 (s, 1H),13.14 (br s, 1H). MS m/z 198 [M+H]⁺

Preparation 249 Benzyl [2-(aminomethyl)phenyl]methylcarbamatehydrochloride

To a solution of tert-butyl [2-(methylamino)benzyl]carbamate(WO2004/046107A1, 1.7 g, 7.2 mmol) in THF (25 mL) at 0° C. was added NaH(0.25 g, 10.8 mmol) followed by Cbz-chloride (1.22 g, 7.2 mmol) andcatalytic DMAP (9 mg, 0.72 mmol). The reaction was heated to reflux for2 hours before cooling, quenching with water and extracting into EtOAc.The organic extracts were dried over sodium sulfate, concentrated invacuo and purified by silica gel column chromatography. The residue wasdissolved in MeOH (10 mL) and 20% HCl in dioxane (10 mL) was added withstirring at room temperature for 18 hours. The reaction was concentratedin vacuo, and triturated with pentane and ether to afford the titlecompound as the hydrochloride salt (1.2 g, 91%). MS m/z 271 [M+H]⁺

Preparation 250 5-Methoxy-2-(methylamino)benzonitrile

To a solution of 2-amino-5-methoxybenzonitrile (10 g, 67 mmol) in DMF(100 mL) was added tBuOK (9.46 g, 84 mmol) followed by dimethyl oxalate(11.95 g, 101 mmol) at 0° C. and the reaction was heated to 120° C. for4 hours. The reaction was cooled, quenched by the addition of ice-waterand extracted into EtOAc. The organic layer was collected, washed withbrine, dried over sodium sulfate and concentrated in vacuo. The residuewas purified using silica gel column chromatography to afford the titlecompound (2.9 g, 27%). ¹H NMR (400 MHz, DMSO-d₆): δ ppm 2.72 (s, 3H),3.67 (s, 3H), 5.77 (br s, 1H), 6.67 (d, 1H), 7.06 (d, 1H), 7.11 (dd,1H).

Preparation 251 tert-Butyl2-(2-oxooxazolidine-3-sulfonamido)benzylcarbamate

To a solution of chlorosulfonyl isocyanate (2 g, 8.99 mmol) in dry DCM(20 mL) at 0° C. was added bromoethanol (0.60 mL, 8.19 mmol) and thereaction was stirred at room temperature for 10 minutes. Triethylamine(2.74 mL, 19.79 mmol) in DCM was added followed by(2-amino-benzyl)-carbamic acid tert-butyl ester (1.9 g, 8.19 mmol) andthe reaction stirred at room temperature for 18 hours. The reaction wasquenched with water, extracted into DCM, the organic layer wascollected, dried over sodium sulfate and concentrated in vacuo. Theresidue was purified using silica gel column chromatography eluting with20% EtOAc in hexanes to afford the title compound (2.5 g, 75%). ¹H NMR(400 MHz, DMSO-d₆): δ ppm 1.43 (s, 9H), 3.81 (t, 2H), 4.25 (m, 2H), 4.36(t, 2H), 7.23-7.37 (m, 5H), 10.42 (br s, 1H).

Preparation 252 N-[2-(Aminomethyl)phenyl]-N-methylmethanesulfonamide

To a solution of 1-(2-aminophenyl)ethanone (2 g, 14.8 mmol) in pyridine(20 mL) at 0° C. was added methanesulfonyl chloride (4.6 mL, 59 mmol)and the reaction was stirred at room temperature for 18 hours. Thereaction was concentrated in vacuo and partitioned between 2N HCl andEtOAc. The organic layer was collected, washed with brine, dried oversodium sulfate and concentrated in vacuo to afford the title compound asa brown solid (1.6 g, 51%). ¹H NMR (400 MHz, DMSO-d₆): δ ppm 2.65 (s,3H), 3.18 (s, 3H), 7.23 (t, 1H), 7.58-7.67 (m, 2H), 8.07 (d, 1H). MS m/z212 [M−H]⁻

Preparation 2534-(2-(N-Ethylphenylsulfonamido)-5-methoxybenzyl)amino)-6-(5-fluoro-4-methoxy-2-(2,2,2-trifluoroethyl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide

To a solution of4-((2-(N-ethylphenylsulfonamido)-5-hydroxybenzyl)amino)-6-(5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylicacid (Preparation 259, 300 mg, 0.36 mmol) in anhydrous THF (4 mL) wasadded NMM (0.06 mL, 0.58 mmol) and isobutylchloroformate (0.07 mL, 0.58mmol) at −20° C. and the reaction was stirred at this temperature for 30minutes. Aqueous ammonia (0.2 mL) was added and the reaction stirred atroom temperature for 30 minutes. The reaction was diluted with water andextracted into EtOAc. The organic layer was collected, washed withbrine, dried over sodium sulfate and concentrated in vacuo. The residuewas purified using silica gel column chromatography eluting with 40%EtOAc in hexanes to afford the title compound (180 mg, 60%). MS m/z 818[M+H]⁺

Preparation 2544-((2-(N-Methylphenylsulfonamido)-5-methoxybenzyl)amino)-6-(5-fluoro-4-methoxy-2-(2,2,2-trifluoroethyl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide

The title compound was prepared according to the method described forPreparation 253 using4-((2-(N-methylphenylsulfonamido)-5-hydroxybenzyl)amino)-6-(5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylicacid (Preparation 260). MS m/z 804 [M+H]⁺

Preparation 255 tert-Butyl6-(4-((tert-butoxycarbonyl)oxy)-5-fluoro-2-(2,2,2-trifluoroethyl)phenyl)-4-((2-(methylamino)benzyl)amino)-3-(methylcarbamoyl)-1H-pyrazolo[3,4-d]pyrimidine-1-carboxylate

To a solution of(2-(((6-(5-fluoro-4-methoxy-2-(2,2,2-trifluoroethyl)phenyl)-3-(methylcarbamoyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)methyl)phenyl)(methyl)carbamate(Preparation 256, 80 mg, 0.13 mmol) in anhydrous THF was added borontribromide (0.08 mL, 0.9 mmol) at 0° C. and the reaction was stirred atthis temperature for 2 hours. Another aliquot of boron tribromide wasadded (7eq) and the reaction continued stirring for a further 2 hours.The reaction was concentrated in vacuo and dissolved in DCM. Thesolution was washed with saturated aqueous sodium bicarbonate solution,brine, dried over sodium sulfate and concentrated in vacuo. The residuewas purified using preparative TLC. The residue was dissolved inanhydrous THF (5 mL). To this solution at 0° C. was added triethylamine(0.04 mL, 0.3 mmol) followed by ditertbutyldicarbonate (0.05 mL, 0.21mmol) and catalytic DMAP (1 mg, 0.008 mmol). The reaction was stirred atroom temperature for 1 hour before concentrating in vacuo. The residuewas purified by preparative TLC to afford the title compound. MS m/z 704[M+H]⁺

Preparation 256 tert-Butyl6-(5-fluoro-4-methoxy-2-(2,2,2-trifluoroethyl)phenyl)-4-((2-(methylamino)benzyl)amino)-3-(methylcarbamoyl)-1H-pyrazolo[3,4-d]pyrimidine-1-carboxylate

To a solution of benzyl(2-(((6-(5-fluoro-4-methoxy-2-(2,2,2-trifluoroethyl)phenyl)-3-(methylcarbamoyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)methyl)phenyl)(methyl)carbamate(Preparation 257, 150 mg, 0.23 mmol) in anhydrous THF (5 mL) at 0° C.was added triethylamine (0.08 mL, 0.575 mmol) followed byditertbutyldicarbonate (60 mg, 0.27 mmol) and a catalytic amount ofDMAP. The reaction was stirred at room temperature for 18 hours. Thereaction was partitioned between EtOAc and brine, the organic layercollected, dried over sodium sulfate and concentrated in vacuo. Theresidue was purified using silica gel column chromatography eluting with32% EtOAc in hexanes. The residue was dissolved in ethanol (15 mL) andwas hydrogenated at 30 psi for 1 hour over 10% palladium on carbon (10mg). The reaction was filtered through celite, concentrated in vacuo andpurified using silica gel column chromatography eluting with 32% EtOAcin hexanes to afford the title compound as a white solid (50 mg, 80%).MS m/z 618 [M+H]⁺

Preparation 257 Benzyl(2-(((6-(5-fluoro-4-methoxy-2-(2,2,2-trifluoroethyl)phenyl)-3-(methylcarbamoyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)methyl)phenyl)(methyl)carbamate

The title compound was prepared according to the method described forPreparation 18 using benzyl(2-(((6-(5-fluoro-4-methoxy-2-(2,2,2-trifluoroethyl)phenyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)methyl)phenyl)(methyl)carbamate(Preparation 284). ¹H NMR (400 MHz, DMSO-d₆): δ ppm 2.82 (s, 3H), 3.17(s, 3H), 3.88 (s, 3H), 4.26-4.39 (m, 2H), 4.65 (m, 1H), 4.79-4.90 (m,2H), 5.03 (m, 1H), 7.09-7.42 (m, 10H), 7.70 (m, 1H), 8.83 (t, 1H), 9.90(t, 1H), 14.07 (s, 1H).

The following Preparations (Preparations 258-261) were preparedaccording to the method described for Preparation 11 using theappropriate pyrazolopyrimidine as described below.

Preparation Number Name Data/SM 258 6-(2-ethyl-5-fluoro-4-((2- MS m/z835 [M − H]⁻ (trimethylsilyl)ethoxy)methoxy)phenyl)-N-(2-(((6-(2-ethyl-5-fluoro-4-((2- 4-((2-(N-(trimethylsilyl)ethoxy)methoxy)phenyl)-3-methylphenylsulfonamido)benzyl)amino)-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)- 1-((2-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)- (trimethylsilyl)-methyl)phenyl)-N- ethoxy)methyl)-1H- methylbenzenesulfonamide(Preparation pyrazolo-[3,4-d]pyrimidine- 262). 3-carboxylic acid 2594-((2-(N- MS m/z 819 [M − H]⁻ ethylphenylsulfonamido)-5-N-ethyl-N-(2-(((6-(5-fluoro-4-methoxy-2- methoxybenzyl)amino)-6-(5-(2,2,2-trifluoroethyl)phenyl)-3-iodo-1-((2- fluoro-4-methoxy-2-(2,2,2-(trimethylsilyl)ethoxy)methyl)-1H- trifluoroethyl)phenyl)-1-((2-pyrazolo[3,4-d]pyrimidin-4- (trimethylsilyl)ethoxy)methyl)-yl)amino)methyl)-4-methoxy- 1H-pyrazolo[3,4- phenyl)benzenesulfonamide(Preparation d]pyrimidine-3-carboxylic 266). acid 2606-(5-fluoro-4-methoxy-2- MS m/z 805 [M + H]⁺(2,2,2-trifluoroethyl)phenyl)- N-methyl-N-(2-(((6-(5-fluoro-4-methoxy-2-4-((5-methoxy-2-(N- (2,2,2-trifluoroethyl)phenyl)-3-iodo-1-((2-methylphenylsulfonamido)benzyl)amino)-(trimethylsilyl)ethoxy)methyl)-1H- 1-((2- pyrazolo[3,4-d]pyrimidin-4-(trimethylsilyl)ethoxy)methyl)- yl)amino)methyl)-4- 1H-pyrazolo[3,4-methoxyphenyl)benzenesulfonamide d]pyrimidine-3-carboxylic (Preparation267). acid 261 6-(5-fluoro-2-(2,2,2-trifluoro- MS m/z 889 [M − H]⁻ethyl)-4-((2-(trimethylsilyl)-N-(2-(((6-(5-fluoro-2-(2,2,2-trifluoroethyl)- ethoxy)methoxy)phenyl)-4-4-((2- ((2-(N- (trimethylsilyl)ethoxy)methoxy)phenyl)-3-methylphenylsulfonamido)benzyl)amino)-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)- 1-((2-1H-pyrazolo[3,4-d]pyrimidin-4- (trimethylsilyl)ethoxy)-yl)amino)methyl)phenyl)-N- methyl)-1H-pyrazolo[3,4-methylbenzenesulfonamide d]pyrimidine-3-carboxylic (Preparation 264).acid

Preparation 262N-(2-(((6-(2-Ethyl-5-fluoro-4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)methyl)phenyl-N-methylbenzenesulfonamide

To a suspension of NaH (0.163 g, 6.79 mmol) in dry DMF (50 mL) was addedN-(2-(((6-(4-((tert-butyldimethylsilyl)oxy)-2-ethyl-5-fluorophenyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)methyl)phenyl)-N-methylbenzenesulfonamide(Preparation 274, 2.1 g, 2.71 mmol) at 0° C. and the reaction stirredfor 15 minutes. SEMCl was then added (1.06 mL, 5.97 mmol) and thereaction allowed to warm to room temperature. The reaction was quenchedwith water, partioned between EtOAc and brine, the organic layercollected, dried over sodium sulfate and concentrated in vacuo. Theresidue was purified using silica gel column chromatography to affordthe title compound (760 mg, 43%). ¹H NMR (400 MHz, DMSO-d₆): δ ppm −0.10(s, 9H), −0.05 (s, 9H), 0.89 (m, 4H), 1.03 (t, 3H), 2.88 (m, 2H), 3.09(s, 3H), 3.57 (t, 2H), 3.73 (t, 2H), 4.93 (m, 1H), 5.16 (m, 1H), 5.31(s, 2H), 5.61 (s, 2H), 6.54 (m, 1H), 7.10 (d, 1H), 7.17 (t, 1H), 7.30(t, 1H), 7.42 (m, 1H), 7.46 (m, 1H), 7.62-7.67 (m, 4H), 7.76 (m, 1H),7.95 (s, 1H). MS m/z 919 [M+H]⁺

The following Preparations (Preparations 263-268) were preparedaccording to the method described for Preparation 131 using either DMFor THF and the appropriate pyrazolopyrimidine as described below.

Preparation Number Name Data/SM 263 N-ethyl-N-(2-(((6-(5-fluoro-2- MSm/z 925 [M + H]⁺ (2,2,2-trifluoroethyl)-4-((2-N-(2-(((6-(4-((tert-butyldimethylsilyl)oxy)-(trimethylsilyl)ethoxy)methoxy)phenyl)-5-fluoro-2-(2,2,2-trifluoroethyl)phenyl)-3- 3-iodo-1-((2-iodo-1H-pyrazolo[3,4-d]pyrimidin-4- (trimethylsilyl)ethoxy)methyl)-yl)amino)methyl)phenyl)-N- 1H-pyrazolo-[3,4- ethylmethanesulfonamided]pyrimidin-4-yl)amino)- (Preparation 280).methyl)phenyl)methanesulfonamide 264 N-(2-(((6-(5-fluoro-2-(2,2,2- MSm/z 973 [M + H]⁺ trifluoroethyl)-4-((2-N-(2-(((6-(4-((tert-butyldimethylsilyl)oxy)- (trimethyl-5-fluoro-2-(2,2,2-trifluoroethyl)phenyl)-3-silyl)ethoxy)methoxy)phenyl)- iodo-1H-pyrazolo[3,4-d]pyrimidin-4-3-iodo-1-((2- yl)amino)methyl)phenyl)-N- (trimethylsilyl)ethoxy)methyl)-methylbenzenesulfonamide 1H-pyrazolo[3,4- (Preparation 278).d]pyrimidin-4- yl)amino)methyl)phenyl)-N- methylbenzenesulfonamide 265N-(2-(((6-(4-((tert- Taken on directly to the next step.butyldimethylsilyl)oxy)-5- N-(2-(((6-(4-((tert-butyldimethylsilyl)oxy)-fluoro-2-(2,2,2- 5-fluoro-2-(2,2,2-trifluoroethyl)phenyl)-3-trifluoroethyl)phenyl)-3-iodo- iodo-1H-pyrazolo[3,4-d]pyrimidin-4-1-((2- yl)amino)methyl)phenyl)-N-(2-((tert-(trimethylsilyl)ethoxy)methyl)- butyldimethylsilyl)oxy)1H-pyrazolo[3,4-d]pyrimidin- ethyl)methanesulfonamide4-yl)amino)methyl)phenyl)-N- (Preparation 279).(2-((tert-butyldimethylsilyl)- oxy)ethyl)methanesulfonamide 266N-ethyl-N-(2-(((6-(5-fluoro-4- MS m/z 901 [M + H]⁺methoxy-2-(2,2,2-trifluoro- N-ethyl-N-(2-(((6-(5-fluoro-4-methoxy-2-ethyl)phenyl)-3-iodo-1-((2- (2,2,2-trifluoroethyl)phenyl)-3-iodo-1H-(trimethylsilyl)ethoxy)methyl)- pyrazolo[3,4-d]pyrimidin-4-1H-pyrazolo[3,4-d]pyrimidin- yl)amino)methyl)-4- 4-yl)amino)methyl)-4-methoxyphenyl)benzenesulfonamide methoxy- (Preparation 281).phenyl)benzenesulfonamide 267 N-methyl-N-(2-(((6-(5-fluoro- MS m/z 885[M − H]⁻ 4-methoxy-2-(2,2,2-trifluoro-N-methyl-N-(2-(((6-(5-fluoro-4-methoxy-2- ethyl)phenyl)-3-iodo-1-((2-(2,2,2-trifluoroethyl)phenyl)-3-iodo-1H- (trimethylsilyl)ethoxy)methyl)-pyrazolo[3,4-d]pyrimidin-4- 1H-pyrazolo[3,4-d]pyrimidin-yl)amino)methyl)-4- 4-yl)amino)methyl)-4-methoxyphenyl)benzenesulfonamide methoxy- (Preparation 282).phenyl)benzenesulfonamide 268 N-(4-fluoro-2-(((6-(5-fluoro-4- MS m/z 813[M + H]⁺ methoxy-2-(2,2,2- N-(4-fluoro-2-(((6-(5-fluoro-4-methoxy-2-trifluoroethyl)phenyl)-3-iodo- (2,2,2-trifluoroethyl)phenyl)-3-iodo-1H-1-((2- pyrazolo[3,4-d]pyrimidin-4- (trimethylsilyl)ethoxy)methyl)-yl)amino)methyl)phenyl)-N- 1H-pyrazolo[3,4-d]pyrimidin-methylmethanesulfonamide (Preparation 4-yl)amino)methyl)phenyl)-N- 283).methylmethanesulfonamide

Preparation 2696-(5-Fluoro-4-methoxy-2-(2,2,2-trifluoroethyl)phenyl)-4-((5-methoxy-2-(N-methylmethylsulfonamido)benzyl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylicacid

The title compound was prepared according to the methods described forPreparations 262 and 258 usingN-(2-(((6-(5-fluoro-4-methoxy-2-(2,2,2-trifluoro-ethyl)phenyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)methyl)-4-methoxyphenyl)-N-methylmethanesulfonamide(Preparation 273). MS m/z 743 [M+H]

Preparation 2706-(5-Fluoro-4-methoxy-2-(2,2,2-trifluoroethyl)phenyl)-4-((2-(N-methylmethylsulfonamido)-benzyl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylicacid

The title compound was prepared according to the methods described forPreparations 262 and 258 usingN-(2-(((6-(5-fluoro-4-methoxy-2-(2,2,2-trifluoroethyl)phenyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)methyl)phenyl)-N-methylmethanesulfonamide(Preparation 275). MS m/z 713 [M+H]

Preparation 271N-(2-((6-(5-Fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)methyl)-4-hydroxyphenyl)-N-methylmethanesulfonamide

To a solution ofN-(2-(((6-(5-fluoro-4-methoxy-2-(2,2,2-trifluoroethyl)phenyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)methyl)-4-methoxyphenyl)-N-methylmethanesulfonamide (Preparation 273, 300 mg, 0.43 mmol) in DCM (10 mL) at 0° C.was added boron tribromide (0.28 mL, 3.02 mmol). The reaction wasstirred at room temperature for 30 minutes before concentrating invacuo. The residue was partitioned between ethyl acetate and water, theorganic layer was collected, dried and concentrated in vacuo. Theresidue was purified using silica gel column chromatography eluting with10% MeOH in DCM to afford the title compound as a white solid (250 mg,87%). ¹H NMR (400 MHz, DMSO-d₆): δ ppm 3.02 (s, 3H), 3.12 (s, 3H),4.11-4.21 (m, 2H), 4.80 (m, 1H), 4.94 (m, 1H), 6.67 (m, 1H), 6.76 (m,1H), 6.97 (m, 1H), 7.29-7.33 (m, 2H), 7.57 (m, 1H), 9.58 (s, 1H), 10.36(s, 1H), 13.88 (s, 1H). MS m/z 667 [M+H]⁺

The following Preparations (Preparations 272-284) were preparedaccording to the method described for Preparation 137 in an organicsolvent such as DCM or DMF and using the appropriate pyrazolopyrimidineas described below.

Preparation Number Name Data/SM 272 N-(2-(((6-(4-(benzyloxy)-2- MS m/z687 [M + H]⁺ ethyl-5-fluorophenyl)-3-iodo-N-(2-(((6-(4-(benzyloxy)-2-ethyl-5- 1H-pyrazolo[3,4-d]pyrimidin-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin- 4-yl)amino)methyl)phenyl)-4-yl)amino)methyl)phenyl)-N- N- methylmethanesulfonamide (Preparationmethylmethanesulfonamide 285). 273 N-(2-(((6-(5-fluoro-4- MS m/z 695[M + H]⁺ methoxy-2-(2,2,2- N-(2-(((6-(5-fluoro-4-methoxy-2-(2,2,2-trifluoroethyl)phenyl)-3-iodo- trifluoroethyl)phenyl)-1H-pyrazolo[3,4-1H-pyrazolo[3,4-d]pyrimidin- d]pyrimidin-4-yl)amino)methyl)-4-4-yl)amino)methyl)-4- methoxyphenyl)-N- methoxyphenyl)-N-methylmethanesulfonamide (Preparation methylmethanesulfonamide 286). 274N-(2-(((6-(4-((tert- MS m/z 773 [M + H]⁺ butyldimethylsilyl)oxy)-2- ¹HNMR (400 MHz, DMSO-d₆): δ ppm ethyl-5-fluoro-phenyl)-3- 0.18 (s, 6H),0.93 (t, 3H), 0.95 (s, 9H), 2.81 (q, iodo-1H-pyrazolo[3,4- 2H), 3.06 (s,3H), 4.89 (m, 1H), 5.17 (m, d]pyrimidin-4-yl)amino)- 1H), 6.53 (d, 1H),7.14 (d, 1H), 7.18 (m, methyl)phenyl)-N- 1H), 7.31 (m, 1H), 7.33-7.45(m, 3H), methylbenzenesulfonamide 7.61-7.66 (m, 4H), 7.76 (m, 1H).N-(2-(((6-(4-((tert-butyldimethylsilyl)oxy)-2-ethyl-5-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)methyl)phenyl)-N- methylbenzenesulfonamide(Preparation 294). 275 N-(2-(((6-(5-fluoro-4- MS m/z 665 [M + H]⁺methoxy-2-(2,2,2- N-(2-(((6-(5-fluoro-4-methoxy-2-(2,2,2-trifluoroethyl)phenyl)-3-iodo- trifluoroethyl)phenyl)-1H-pyrazolo[3,4-1H-pyrazolo[3,4-d]pyrimidin- d]pyrimidin-4-yl)amino)methyl)phenyl)-N-4-yl)amino)-methyl)phenyl)- methylmethanesulfonamide (PreparationN-methyl- 287). methanesulfonamide 276 N-(2-(((6-(4-(benzyloxy)-5- MSm/z 741 [M + H]⁺ fluoro-2-(2,2,2-N-(2-(((6-(4-(benzyloxy)-5-fluoro-2-(2,2,2-trifluoroethyl)phenyl)-3-iodo- trifluoroethyl)phenyl)-1H-pyrazolo[3,4-1H-pyrazolo[3,4-d]pyrimidin- d]pyrimidin-4-yl)amino)methyl)phenyl)-N-4-yl)amino)methyl)phenyl)- methylmethanesulfonamide (Preparation N-288). methylmethanesulfonamide 277 N-(3-(((6-(5-fluoro-4- MS m/z 665 [M− H]⁻ methoxy-2-(2,2,2- N-(3-(((6-(5-fluoro-4-methoxy-2-(2,2,2-trifluoroethyl)phenyl)-3-iodo- trifluoroethyl)phenyl)-1H-pyrazolo[3,4-1H-pyrazolo[3,4-d]pyrimidin- d]pyrimidin-4-yl)amino)methyl)pyrazin-2-4-yl)amino)-methyl)pyrazin- yl)-N-methylmethanesulfonamide 2-yl)-N-(Preparation 289). methylmethanesulfonamide 278 N-(2-(((6-(4-((tert- MSm/z 827 [M + H]⁺ butyldimethylsilyl)oxy)-5-N-(2-(((6-(4-((tert-butyldimethylsilyl)oxy)-5- fluoro-2-(2,2,2-fluoro-2-(2,2,2-trifluoroethyl)phenyl)-1H-trifluoroethyl)phenyl)-3-iodo- pyrazolo[3,4-d]pyrimidin-4-1H-pyrazolo[3,4-d]pyrimidin- yl)amino)methyl)phenyl)-N-4-yl)amino)-methyl)phenyl)- methylbenzenesulfonamide (Preparation N-295). methylbenzenesulfonamide 279 N-(2-(((6-(4-((tert- MS m/z 909 [M +H]⁺ butyldimethylsilyl)oxy)-5-N-(2-(((6-(4-((tert-butyldimethylsilyl)oxy)-5- fluoro-2-(2,2,2-fluoro-2-(2,2,2-trifluoroethyl)phenyl)-1H-trifluoroethyl)phenyl)-3-iodo- pyrazolo[3,4-d]pyrimidin-4-1H-pyrazolo[3,4-d]pyrimidin- yl)amino)methyl)phenyl)-N-(2-((tert-4-yl)amino)-methyl)phenyl)-butyldimethylsilyl)oxy)ethyl)methanesulfonamideN-(2-((tert-butyldimethyl- (Preparation 296).silyl)oxy)ethyl)methanesulfon- amide 280 N-(2-(((6-(4-((tert- MS m/z 779[M + H]⁺ butyldimethylsilyl)oxy)-5-N-(2-(((6-(4-((tert-butyldimethylsilyl)oxy)-5- fluoro-2-(2,2,2-fluoro-2-(2,2,2-trifluoroethyl)phenyl)-1H-trifluoroethyl)phenyl)-3-iodo- pyrazolo[3,4-d]pyrimidin-4-1H-pyrazolo[3,4-d]pyrimidin- yl)amino)methyl)phenyl)-N-4-yl)amino)methyl)phenyl)- ethylmethanesulfonamide (PreparationN-ethylmethanesulfonamide 297). 281 N-ethyl-N-(2-(((6-(5-fluoro- MS m/z771 [M + H]⁺ 4-methoxy-2-(2,2,2-N-ethyl-N-(2-(((6-(5-fluoro-4-methoxy-2- trifluoroethyl)phenyl)-3-iodo-(2,2,2-trifluoroethyl)phenyl)-1H- 1H-pyrazolo[3,4-d]pyrimidin-pyrazolo[3,4-d]pyrimidin-4-4-yl)amino)methyl)-4-methoxyphenyl)benzenesulfonamideyl)amino)methyl)-4- methoxyphenyl)benzenesulfonamide (Preparation 290).282 N-methyl-N-(2-(((6-(5-fluoro- MS m/z 757 [M + H]⁺4-methoxy-2-(2,2,2- N-methyl-N-(2-(((6-(5-fluoro-4-methoxy-2-trifluoroethyl)phenyl)-3-iodo- (2,2,2-trifluoroethyl)phenyl)-1H-1H-pyrazolo[3,4-d]pyrimidin- pyrazolo[3,4-d]pyrimidin-4-4-yl)amino)methyl)-4-methoxyphenyl)benzenesulfonamideyl)amino)methyl)-4- methoxyphenyl)benzenesulfonamide (Preparation 291).283 N-(4-fluoro-2-(((6-(5-fluoro- MS m/z 683 [M + H]⁺4-methoxy-2-(2,2,2-trifluoro- N-(4-fluoro-2-(((6-(5-fluoro-4-methoxy-2-ethyl)phenyl)-3-iodo-1H- (2,2,2-trifluoroethyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4- pyrazolo[3,4-d]pyrimidin-4-yl)amino)methyl)phenyl)-N- yl)amino)methyl)phenyl)-N-methylmethanesulfonamide methylmethanesulfonamide (Preparation 292). 284Benzyl (2-(((6-(5-fluoro-4- MS m/z 721 [M + H]⁺methoxy-2-(2,2,2-trifluoro- Benzyl (2-(((6-(5-fluoro-4-methoxy-2-ethyl)phenyl)-3-iodo-1H- (2,2,2-trifluoroethyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4- pyrazolo[3,4-d]pyrimidin-4- yl)amino)-yl)amino)methyl)- methyl)phenyl)(methyl)carbamatephenyl)(methyl)carbamate (Preparation 293).

The following Preparations (Preparations 285-293) were preparedaccording to the method described for Preparation 140 using either 4MHCl in dioxane or cHCl in MeOH with the appropriate pyrazolopyrimidineas described below.

Preparation Number Name Data/SM 285 N-(2-(((6-(4-(benzyloxy)-2- MS m/z561 [M + H]⁺ ethyl-5-fluorophenyl)-1H-N-(2-(((6-(4-(benzyloxy)-2-ethyl-5- pyrazolo[3,4-d]pyrimidin-4-fluorophenyl)-1-(tetrahydro-2H-pyran-2-yl)- yl)amino)methyl)phenyl)-N-1H-pyrazolo[3,4-d]pyrimidin-4- methylmethanesulfonamideyl)amino)methyl)phenyl)-N- methylmethanesulfonamide (Preparation 299).286 N-(2-(((6-(5-fluoro-4- MS m/z 569 [M + H]⁺ methoxy-2-(2,2,2-N-(2-(((6-(5-fluoro-4-methoxy-2-(2,2,2- trifluoroethyl)phenyl)-1H-trifluoroethyl)phenyl)-1-(tetrahydro-2H- pyrazolo[3,4-d]pyrimidin-4-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4- yl)amino)methyl)-4-yl)amino)methyl)-4-methoxyphenyl)-N- methoxyphenyl)-N-methylmethanesulfonamide (Preparation methylmethanesulfonamide 300). 287N-(2-(((6-(5-fluoro-4- MS m/z 539 [M + H]⁺ methoxy-2-(2,2,2-N-(2-(((6-(5-fluoro-4-methoxy-2-(2,2,2- trifluoroethyl)phenyl)-1H-trifluoroethyl)phenyl)-1-(tetrahydro-2H- pyrazolo[3,4-d]pyrimidin-4-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4- yl)amino)methyl)phenyl)-N-yl)amino)methyl)phenyl)-N- methylmethanesulfonamidemethylmethanesulfonamide (Preparation 302). 288N-(2-(((6-(4-(benzyloxy)-5- MS m/z 615 [M + H]⁺ fluoro-2-(2,2,2-N-(2-(((6-(4-(benzyloxy)-5-fluoro-2-(2,2,2- trifluoroethyl)phenyl)-1H-trifluoroethyl)phenyl)-1-(tetrahydro-2H- pyrazolo[3,4-d]pyrimidin-4-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4- yl)amino)methyl)phenyl)-N-yl)amino)methyl)phenyl)-N- methylmethanesulfonamidemethylmethanesulfonamide (Preparation 303). 289 N-(3-(((6-(5-fluoro-4-MS m/z 541 [M + H]⁺ methoxy-2-(2,2,2-N-(3-(((6-(5-fluoro-4-methoxy-2-(2,2,2- trifluoroethyl)phenyl)-1H-trifluoroethyl)phenyl)-1-(tetrahydro-2H- pyrazolo[3,4-d]pyrimidin-4-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4- yl)amino)methyl)pyrazin-2-yl)amino)methyl)pyrazin-2-yl)-N- yl)-N- methylmethanesulfonamide(Preparation methylmethanesulfonamide 304). 290N-ethyl-N-(2-(((6-(5-fluoro- MS m/z 645 [M + H]⁺ 4-methoxy-2-(2,2,2-N-ethyl-N-(2-(((6-(5-fluoro-4-methoxy-2- trifluoroethyl)phenyl)-1H-(2,2,2-trifluoroethyl)phenyl)-1-(tetrahydro- pyrazolo[3,4-d]pyrimidin-4-2H-pyran-2-yl)-1H-pyrazolo[3,4- yl)amino)methyl)-4-d]pyrimidin-4-yl)amino)methyl)-4- methoxy-methoxyphenyl)benzenesulfonamide phenyl)benzenesulfonamide (Preparation308). 291 N-methyl-N-(2-(((6-(5-fluoro- MS m/z 631 [M + H]⁺4-methoxy-2-(2,2,2- N-methyl-N-(2-(((6-(5-fluoro-4-methoxy-2-trifluoroethyl)phenyl)-1H- (2,2,2-trifluoroethyl)phenyl)-1-(tetrahydro-pyrazolo[3,4-d]pyrimidin-4- 2H-pyran-2-yl)-1H-pyrazolo[3,4-yl)amino)methyl)-4-methoxyphenyl)benzenesulfonamided]pyrimidin-4-yl)amino)methyl)-4- methoxyphenyl)benzenesulfonamide(Preparation 309). 292 N-(4-fluoro-2-(((6-(5-fluoro- MS m/z 557 [M + H]⁺4-methoxy-2-(2,2,2- N-(4-fluoro-2-(((6-(5-fluoro-4-methoxy-2-trifluoroethyl)phenyl)-1H- (2,2,2-trifluoroethyl)phenyl)-1-(tetrahydro-pyrazolo[3,4-d]pyrimidin-4- 2H-pyran-2-yl)-1H-pyrazolo[3,4-yl)amino)methyl)phenyl)-N- d]pyrimidin-4-yl)amino)methyl)phenyl)-N-methylmethanesulfonamide methylmethanesulfonamide (Preparation 310). 293Benzyl (2-(((6-(5-fluoro-4- MS m/z 595 [M + H]⁺ methoxy-2-(2,2,2- Benzyl(2-(((6-(5-fluoro-4-methoxy-2- trifluoroethyl)phenyl)-1H-(2,2,2-trifluoroethyl)phenyl)-1-(tetrahydro- pyrazolo[3,4-d]pyrimidin-4-2H-pyran-2-yl)-1H-pyrazolo[3,4- yl)amino)methyl)phenyl)(methyl)carbamated]pyrimidin-4- yl)amino)methyl)phenyl)(methyl)carbamate (Preparation311).

Preparation 294N-(2-(((6-(4-((tert-Butyldimethylsilyl)oxy)-2-ethyl-5-fluorophenyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)methyl)phenyl)-N-methylbenzenesulfonamide

N-(2-(((6-(2-ethyl-5-fluoro-4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)methyl)phenyl)-N-methylbenzenesulfonamide (Preparation 301, 2.6 g, 3.48 mmol) was treated with TFA (5mL) and the reaction stirred at room temperature for 30 minutes beforeconcentrating in vacuo. The residue was diluted with methanol (20 mL),cooled in ice-water and treated with a drop-wise addition of ethylenediamine until the solution became basic. The solution was concentratedin vacuo and purified using silica gel column chromatography elutingwith EtOAc. The residue (1.7 g, 3.19 mmol) was dissolved in anhydrousTHF (10 mL) and 2,6 lutidine (0.55 mL, 4.78 mmol) was added followed byTBDMS-triflate (0.88 mL, 3.83 mmol) at 0° C. The reaction was stirredfor 18 hours. The reaction was concentrated in vacuo and partitionedbetween water and ethyl acetate. The organic phase was washed withbrine, dried over sodium sulfate, concentrated in vacuo and purified bysilica gel column chromatography eluting with 20% EtOAc in hexanes toafford the title compound as a white solid (1.9 g, 92%). MS m/z 647[M+H]⁺

The following Preparations (Preparations 295-297) were preparedaccording to the method described for Preparation 294 using theappropriate pyrazolopyrimidine as described below.

Preparation Number Name SM 295 N-(2-(((6-(4-((tert- MS m/z 701 [M + H]⁺butyldimethylsilyl)oxy)-5-N-(2-(((6-(5-fluoro-2-(2,2,2-trifluoroethyl)-4-fluoro-2-(2,2,2-trifluoro- ((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-ethyl)phenyl)-1H-pyrazolo[3, 1-(tetrahydro-2H-pyran-2-yl)-1H-4-d]pyrimidin-4- pyrazolo[3,4-d]pyrimidin-4- yl)amino)methyl)phenyl)-N-yl)amino)methyl)phenyl)-N- methylbenzenesulfonamidemethylbenzenesulfonamide (Preparation 305). 296 N-(2-(((6-(4-((tert- MSm/z 783 [M + H]⁺ butyldimethylsilyl)oxy)-5-N-(2-(((6-(5-fluoro-2-(2,2,2-trifluoroethyl)-4-fluoro-2-(2,2,2-trifluoro- ((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-ethyl)phenyl)-1H-pyrazolo[3, 1-(tetrahydro-2H-pyran-2-yl)-1H-4-d]pyrimidin-4- pyrazolo[3,4-d]pyrimidin-4- yl)amino)methyl)phenyl)-yl)amino)methyl)phenyl)-N-(2-((tetrahydro- N-(2-((tert-butyldimethyl-2H-pyran-2- silyl)oxy)ethyl)methanesulfonamideyl)oxy)ethyl)methanesulfonamide (Preparation 316). 297N-(2-(((6-(4-((tert-butyl- MS m/z 653 [M + H]⁺dimethylsilyl)oxy)-5-fluoro- N-ethyl-N-(2-(((6-(5-fluoro-2-(2,2,2-2-(2,2,2-trifluoro- trifluoroethyl)-4-((2- ethyl)phenyl)-1H-(trimethylsilyl)ethoxy)methoxy)phenyl)-1- pyrazolo[3,4-d]pyrimidin-4-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4- yl)amino)methyl)phenyl)-N-d]pyrimidin-4- ethylmethanesulfonamideyl)amino)methyl)phenyl)methanesulfonamide (Preparation 307).

Preparation 2984-Chloro-6-(5-fluoro-2-(2,2,2-trifluoroethyl)-4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidine

To a solution of4-(benzyloxy)-6-(5-fluoro-2-(2,2,2-trifluoroethyl)-4-((2-(trimethyl-silyl)ethoxy)methoxy)phenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidine(Preparation 306, 12.5 g, 19.75 mmol) in THF (100 mL) was added 10%palladium on carbon (1.5 g) and the reaction was hydrogenated at 50 psifor 18 hours. The reaction was filtered and the filtrate wasconcentrated in vacuo. The residue was purified using silica gel columnchromatography to afford a white solid. 5 g (9.22 mmol) was dissolved inDMF (50 mL) and cooled to 0° C. Oxalyl chloride (7.96 mL, 92 mmol) wasadded and the reaction stirred at room temperature for 6 hours. Thereaction was quenched with water and extracted into EtOAc. The organiclayer was collected, dried over sodium sulfate and concentrated invacuo. The residue was purified using silica gel column chromatographyto afford the title compound (1.2 g, 23%). MS m/z 561 [M+H]⁺

Preparation 299N-(2-(((6-(4-(Benzyloxy)-2-ethyl-5-fluorphenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)methyl)phenyl)-N-methylmethanesulfonamide

A solution of palladium acetate (42 mg, 0.19 mmol) and S-Phos (77 mg,0.19 mmol) in ethanol (10 mL) was heated at 50° C. for 45 minutes afterpurging with nitrogen (Solution A). Meanwhile a solution ofN-(2-(((6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)methyl)phenyl)-N-methylmethanesulfonamide(Preparation 312, 1.7 g, 3.77 mmol) in ethanol (30 mL) was treated with2-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(Preparation 323, 1.83 g, 5.13 mmol) and an aqueous solution ofpotassium phosphate (1.6 g, 7.54 mmol) in water (12 mL) This solutionwas purged with nitrogen for 10 minutes (Solution B). Solution A wasadded to Solution B and the mixture heated at 80° C. for 18 hours. Thereaction was cooled, concentrated in vacuo. The resulting black solidwas suspended in ethyl acetate filtered through celite. The filtrate wasconcentrated in vacuo, the residue was taken up in EtOAc, washed withwater, brine, dried over sodium sulfate and concentrated in vacuo. Theresidue was purified by silica gel column chromatography eluting with40% EtOAc in hexanes to afford the title compound as a fluffy whitesolid (1.58 g, 65%). ¹H NMR (400 MHz, DMSO-ds): δ ppm 1.02 (m, 3H), 1.55(m, 2H), 1.74 (m, 1H), 1.85 (m, 1H), 2.00 (m, 1H), 2.43 (m, 1H), 2.84(m, 2H), 3.07 (s, 3H), 3.16 (s, 3H), 3.63 (m, 1H), 3.93 (m, 1H), 4.75(br m, 1H), 5.00 (br m, 1H), 5.22 (s, 2H), 5.85 (m, 1H), 7.10 (m, 1H),7.30-7.54 (m, 10H), 8.22 (s, 1H), MS m/z 645 [M+H]⁺

The following Preparations (Preparations 300-311) were preparedaccording to the method described for Preparation 299 using theappropriate chloro-pyrazolopyrimidine and arylboronic ester as describedbelow.

Preparation Number Name Data SM 300 N-(2-(((6-(5-fluoro-4- ¹H NMR (400MHz, 2-[5-fluoro-4- methoxy-2-(2,2,2- DMSO-d₆): δ ppm methoxy-2-(2,2,2-trifluoroethyl)phenyl)-1- 1.56 (m, 2H), 1.73 (m, 1H),trifluoroethyl)phenyl]- (tetrahydro-2H-pyran-2- 1.89 (m, 1H),4,4,5,5-tetramethyl- yl)-1H-pyrazolo[3,4- 1.98-2.01 (m, 1H),1,3,2-dioxaborolane d]pyrimidin-4- 2.42-2.50 (m, 1H), 3.04 (s,(WO2013/014567A1) yl)amino)methyl)-4- 3H), 3.13 (s, 3H), andN-(2-(((6-chloro- methoxyphenyl)-N- 3.66 (m, 4H), 3.88 (s, 3H),1-(tetrahydro-2H- methylmethanesulfonamide 3.93 (m, 1H), pyran-2-yl)-1H-4.29-4.34 (m, 2H), 4.70 (m, pyrazolo[3,4- 1H), 5.00 (m, 1H),d]pyrimidin-4- 5.87 (m, 1H), 6.91 (m, 2H), yl)amino)methyl)-4- 7.23 (d,1H), 7.48 (d, methoxyphenyl)-N- 1H), 7.78 (m, 1H),methylmethanesulfonamide 8.24 (s, 1H), 8.85 (t, 1H). (Preparation 314).301 N-(2-(((6-(2-ethyl-5- MS m/z 747 [M + H]⁺ N-(2-(((6-chloro-1-fluoro-4-((2-(trimethyl- (tetrahydro-2H-pyran-silyl)ethoxy)methoxy)phenyl)- 2-yl)-1H-pyrazolo[3,4- 1-(tetrahydro-2H-d]pyrimidin-4- pyran-2-yl)-1H- yl)amino)methyl)phenyl)- pyrazolo[3,4- N-d]pyrimidin-4- methylbenzenesulfonamide yl)amino)methyl)phenyl)-(Preparation N- 313) and 2-[2-ethyl-5- methylbenzenesulfonamidefluoro-4-[[2- (trimethylsilyl)ethoxy] methoxy]phenyl]-4,4,5,5-tetramethyl- 1,3,2-dioxaborolane (WO2013/014567A1) 302N-(2-(((6-(5-fluoro-4- MS m/z 623 [M + H]⁺ N-(2-(((6-chloro-1-methoxy-2-(2,2,2- ¹H NMR (400 MHz, (tetrahydro-2H-pyran-trifluoroethyl)phenyl)-1- DMSO-d₆): δ ppm 2-yl)-1H-pyrazolo[3,4-(tetrahydro-2H-pyran-2- 1.56 (m, 2H), 1.73 (m, 1H), d]pyrimidin-4-yl)-1H-pyrazolo[3,4- 1.86 (m, 1H), 2.04 (m, yl)amino)methyl)phenyl)-d]pyrimidin-4- 2H), 3.08 (s, 3H), N- yl)amino)methyl)phenyl)- 3.18 (s,3H), 3.65 (m, 1H), methylmethanesulfonamide N- 3.88 (s, 3H),(Preparation methylmethanesulfonamide 3.92-3.96 (m, 1H), 4.30-4.38 (m,312) and 2-[5-fluoro- 2H), 4.75 (br s, 1H), 4-methoxy-2-(2,2,2- 5.00 (brs, 1H), trifluoroethyl)phenyl]- 5.87 (m, 1H), 7.20 (m, 1H),4,4,5,5-tetramethyl- 7.30-7.38 (m, 3H), 1,3,2-dioxaborolane 7.54 (m,1H), (WO2013/014567A1). 7.70-7.73 (m, 1H), 8.24 (s, 1H), 8.90 (t, 1H).303 N-(2-(((6-(4- ¹H NMR (400 MHz, N-(2-(((6-chloro-1-(benzyloxy)-5-fluoro-2- DMSO-d₆): δ ppm (tetrahydro-2H-pyran-(2,2,2-trifluoro- 1.56 (m, 2H), 1.74 (m, 1H), 2-yl)-1H-pyrazolo[3,4-ethyl)phenyl)-1- 1.89 (m, 1H), 2.00 (m, d]pyrimidin-4-(tetrahydro-2H-pyran-2- 2H), 3.07 (s, 3H), yl)amino)methyl)phenyl)-yl)-1H-pyrazolo[3,4- 3.16 (s, 3H), 3.67 (m, 1H), N- d]pyrimidin-4- 3.93(m, 1H), methylmethanesulfonamide yl)amino)methyl)phenyl)- 4.22-4.37 (m,2H), 4.80 (br (Preparation N- m, 1H), 5.00 (br m, 312) and 2-(4-methylmethanesulfonamide 1H), 5.23 (s, 2H), (benzyloxy)-5-fluoro- 5.86(m, 1H), 7.29-7.55 (m, 2-(2,2,2- 10H), 7.73 (m, 1H),trifluoroethyl)phenyl)- 8.24 (s, 1H), 8.89 (t, 4,4,5,5-tetramethyl- 1H).1,3,2-dioxaborolane (Preparation 325). 304 N-(3-(((6-(5-fluoro-4- MS m/z625 [M + H]⁺ N-(3-(((6-chloro-1- methoxy-2-(2,2,2- ¹H NMR (400 MHz,(tetrahydro-2H-pyran- trifluoroethyl)phenyl)-1- DMSO-d₆): δ ppm2-yl)-1H-pyrazolo[3,4- (tetrahydro-2H-pyran-2- 1.56 (m, 2H), 1.65 (m,1H), d]pyrimidin-4- yl)-1H-pyrazolo[3,4- 1.89 (m, 1H), 2.00 (m,yl)amino)methyl)pyrazin- d]pyrimidin-4- 1H), 2.49 (m, 1H), 2-yl)-N-yl)amino)methyl)pyrazin- 3.13 (s, 3H), 3.18 (s, 3H),methylmethanesulfonamide 2-yl)-N-methyl- 3.66 (m, 1H), 3.88 (m,(Preparation methanesulfonamide 4H), 4.25-4.30 (m, 2H), 315) and2-[5-fluoro- 5.03 (m, 2H), 5.85 (m, 4-methoxy-2-(2,2,2- 1H), 7.19 (m,1H), trifluoroethyl)phenyl]- 7.58 (m, 1H), 8.29 (s, 1H),4,4,5,5-tetramethyl- 8.53 (d, 1H), 8.60 (m, 1,3,2-dioxaborolane 1H),9.03 (t, 1H). (WO2013/014567A1) 305 N-(2-(((6-(5-fluoro-2- MS m/z 801[M + H]⁺ N-(2-(((6-chloro-1- (2,2,2-trifluoroethyl)-4-(tetrahydro-2H-pyran- ((2- 2-yl)-1H-pyrazolo[3,4-(trimethylsilyl)ethoxy)methoxy)phenyl)- d]pyrimidin-4- 1-yl)amino)methyl)phenyl)- (tetrahydro-2H-pyran-2- N-methylbenzene-yl)-1H-pyrazolo[3,4- sulfonamide d]pyrimidin-4-yl)amino)- (Preparation313) methyl)phenyl)-N- and (2-{[2-fluoro-4- methyl-(4,4,5,5-tetramethyl- benzenesulfonamide 1,3,2-dioxaborolan-2-yl)-5-(2,2,2- trifluoroethyl)- phenoxy]methoxy}ethyl)(trimethyl)silane(Preparation 150). 306 4-(benzyloxy)-6-(5- MS m/z 634 [M + H]⁺4-(benzyloxy)-6- fluoro-2-(2,2,2- ¹H NMR (400 MHz, chloro-1-(tetrahydro-trifluoroethyl)-4-((2- DMSO-d₆): δ ppm 2H-pyran-2-yl)-1H-(trimethylsilyl)ethoxy)methoxy)phenyl)- −0.01 (s, 9H), 0.89 (t,pyrazolo[3,4- 1- 2H), 1.583 (m, 2H), d]pyrimidine(tetrahydro-2H-pyran-2- 1.75 (m, 1H), (Preparation 322)yl)-1H-pyrazolo[3,4- 1.92-2.05 (m, 2H), 2.44 (m, and (2-{[2-fluoro-4-d]pyrimidine 1H), 3.67 (m, 1H), (4,4,5,5-tetramethyl- 3.77 (t, 2H), 4.01(m, 1H), 1,3,2-dioxaborolan-2- 4.34-4.47 (m, 2H), yl)-5-(2,2,2- 5.39 (s,2H), 5.70 (s, trifluoroethyl)- 2H), 5.95 (m, 1H),phenoxy]methoxy}ethyl)(trimethyl)silane 7.36-7.54 (m, 6H), (Preparation150). 8.01 (m, 1H), 8.34 (s, 1H). 307 N-ethyl-N-(2-(((6-(5- MS m/z 753[M + H]⁺ N-(2-(((6-chloro-1- fluoro-2-(2,2,2- ¹H NMR (400 MHz,(tetrahydro-2H-pyran- trifluoroethyl)-4-((2- DMSO-d₆): δ ppm2-yl)-1H-pyrazolo[3,4- (trimethylsilyl)ethoxy)methoxy)phenyl)- −0.05 (s,9H), 0.80 (t, d]pyrimidin-4- 1- 2H), 1.00 (t, 3H),yl)amino)methyl)phenyl)- (tetrahydro-2H-pyran-2- 1.56 (m, 2H), 1.75 (m,1H), N-ethylmethane- yl)-1H-pyrazolo[3,4- 1.98 (m, 1H), 2.04 (m,sulfonamide d]pyrimidin-4-yl)amino)- 1H), 2.49 (m, 1H), (Preparation317) methyl)phenyl)methane- 3.06 (s, 3H), 3.54 (m, 1H), and(2-{[2-fluoro-4- sulfonamide 3.57-3.76 (m, 4H), (4,4,5,5-tetramethyl-3.93 (m, 1H), 4.20 (m, 1,3,2-dioxaborolan-2- 2H), 4.85 (m, 1H),yl)-5-(2,2,2- 5.00 (m, 1H), 5.32 (s, 2H), trifluoroethyl)- 5.87 (m, 1H),phenoxy]methoxy}ethyl)(trimethyl)silane 7.29-7.39 (m, 4H), 7.52 (m,(Preparation 150). 1H), 7.66 (m, 1H), 8.26 (s, 1H), 8.91 (t, 1H). 308N-ethyl-N-(2-(((6-(5- MS m/z 729 [M + H]⁺ N-(2-(((6-chloro-1-fluoro-4-methoxy-2- ¹H NMR (400 MHz, (tetrahydro-2H-pyran- (2,2,2-DMSO-d₆): δ ppm 2-yl)-1H-pyrazolo[3,4- trifluoroethyl)phenyl)-1- 0.93(t, 3H), 1.57 (m, 2H), d]pyrimidin-4- (tetrahydro-2H-pyran-2- 1.75 (m,1H), 1.90 (m, yl)amino)methyl)-4- yl)-1H-pyrazolo[3,4- 1H), 2.01 (m,1H), methoxyphenyl)-N- d]pyrimidin-4- 2.43 (m, 1H), 3.21 (m, 1H),ethylbenzenesulfonamide yl)amino)methyl)-4- 3.63-3.68 (m, 4H),(Preparation methoxyphenyl)benzene- 3.79-3.96 (m, 4H), 318) and2-[5-fluoro- sulfonamide 4.05-4.35 (m, 2H), 4-methoxy-2-(2,2,2- 4.81 (m,1H), 4.99 (m, trifluoroethyl)phenyl]- 1H), 5.90 (m, 1H),4,4,5,5-tetramethyl- 6.50 (m, 1H), 6.75 (m, 1H), 1,3,2-dioxaborolane6.90 (m, 1H), 7.25 (m, (WO2013/014567A1). 1H), 7.60-7.80 (m, 6H), 8.30(s, 1H), 8.85 (t, 1H). 309 N-methyl-N-(2-(((6-(5- MS m/z 715 [M + H]⁺N-(2-(((6-chloro-1- fluoro-4-methoxy-2- ¹H NMR (400 MHz,(tetrahydro-2H-pyran- (2,2,2- DMSO-d₆): δ ppm 2-yl)-1H-pyrazolo[3,4-trifluoroethyl)phenyl)-1- 1.56 (m, 2H), 1.74 (m, 1H), d]pyrimidin-4-(tetrahydro-2H-pyran-2- 1.98 (m, 1H), 2.00 (m, yl)amino)methyl)-4-yl)-1H-pyrazolo[3,4- 1H), 2.50 (m, 1H), methoxyphenyl)-N- d]pyrimidin-4-3.33 (s, 3H), 3.63-3.68 (m, methylbenzenesulfonamide yl)amino)methyl)-4-4H), 3.88-3.96 (m, 4H), (Preparation methoxyphenyl)benzene- 4.25-4.40(m, 2H), 319) and 2-[5-fluoro- sulfonamide 4.73 (m, 1H), 5.03 (m,4-methoxy-2-(2,2,2- 1H), 5.86 (m, 1H), trifluoroethyl)phenyl]- 6.45 (m,1H), 6.71 (m, 1H), 4,4,5,5-tetramethyl- 6.92 (m, 1H), 7.22 (m,1,3,2-dioxaborolane 1H), 7.61-7.79 (m, 6H), (WO2013/014567A1). 8.26 (s,1H), 8.90 (t, 1H). 310 N-(4-fluoro-2-(((6-(5- ¹H NMR (400 MHz,N-(2-(((6-chloro-1- fluoro-4-methoxy-2- DMSO-d₆): δ ppm(tetrahydro-2H-pyran- (2,2,2- 1.56 (m, 2H), 1.74 (m, 1H),2-yl)-1H-pyrazolo[3,4- trifluoroethyl)phenyl)-1- 1.86 (m, 1H), 2.01 (m,d]pyrimidin-4-yl)amino)methyl)- (tetrahydro-2H-pyran-2- 1H), 2.42 (m,1H), 4-fluoro- yl)-1H-pyrazolo[3,4- 3.08 (s, 3H), 3.16 (s, 3H),phenyl)-N- d]pyrimidin-4- 3.60 (m, 1H), 3.88 (s,methylmethanesulfonamide yl)amino)methyl)phenyl)- 3H), 3.96 (m, 1H),(Preparation 320) N- 4.03-4.31 (m, 2H), and 2-[5-fluoro-4-methylmethanesulfonamide 4.76 (m, 1H), 5.01 (m, methoxy-2-(2,2,2- 1H),5.88 (m, 1H), trifluoroethyl)-phenyl]- 7.11-7.22 (m, 3H),4,4,5,5-tetra-methyl- 7.61-7.71 (m, 2H), 1,3,2-dioxa-borolane 8.24 (s,1H), 8.93 (t, (WO2013/014567A1). 1H). 311 Benzyl (2-(((6-(5-fluoro- ¹HNMR (400 MHz, benzyl (2-(((6-chloro- 4-methoxy-2-(2,2,2- DMSO-d₆): δ ppm1-(tetrahydro-2H- trifluoroethyl)phenyl)-1- 1.56 (m, 2H), 1.73 (m, 1H),pyran-2-yl)-1H- (tetrahydro-2H-pyran-2- 1.85 (m, 1H), 2.01 (m,pyrazolo[3,4- yl)-1H-pyrazolo[3,4- 1H), 2.42 (m, 1H), d]pyrimidin-4-d]pyrimidin-4- 3.18 (s, 3H), 3.69 (m, 1H),yl)amino)methyl)phenyl)(methyl)carbamate yl)amino)methyl)phenyl)- 3.87(s, 3H), 3.93 (m, (Preparation 321) (methyl)carbamate 1H), 4.27-4.50 (m,2H), and 2-[5-fluoro-4- 4.57 (m, 1H), 4.75 (m, methoxy-2-(2,2,2- 1H),4.93-5.03 (m, 2H), trifluoroethyl)phenyl]- 5.86 (m, 1H),4,4,5,5-tetramethyl- 7.12-7.39 (m, 10H), 1,3,2-dioxaborolane 7.71 (m,1H), 8.22 (s, 1H), (WO2013/014567A1). 8.85 (t, 1H).

Preparation 312N-(2-(((6-Chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)methyl)phenyl)-N-methylmethanesulfonamide

To a stirred solution of4,6-dichloro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidine(WO20131014567A1, 3 g, 10.99 mmol) in anhydrous n-butanol (12 mL),containing DIPEA (6.69 mL, 38.45 mmol) was addedN-[2-(aminomethyl)phenyl]-N-methylmethane sulphonamide hydrochloride(WO20101058846A1, 2.76 g, 10.98 mmol) and the reaction was heated in asealed tube at 90° C. for 16 hours. The reaction was concentrated invacuo and the residue partitioned between water & ethyl acetate. Theorganic extracts were washed with brine, dried over sodium sulfate,concentrated in vacuo and triturated with pentane-ether to afford thetitle compound as an off white solid (3.5 g, 71%). ¹H NMR (400 MHz,DMSO-d₆): δ ppm 1.17 (m, 2H), 1.70 (m, 1H), 1.81 (m, 1H), 1.98 (m, 1H),2.36 (m, 1H), 3.09 (s, 3H), 3.25 (s, 3H), 3.66 (m, 1H), 3.94 (m, 1H),4.60 (br m, 1H), 4.90 (br m, 1H), 5.72 (m, 1H), 7.33-7.42 (m, 3H), 7.56(m, 1H), 8.22 (s, 1H), 9.26 (m, 1H).

The following Preparations (Preparations 313-321) were preparedaccording to the method described for Preparation 312 using4,6-dichloro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidine(WO20131014567A1) or other suitable pyrazolopyrimidine and benzylamineas described below.

Preparation Number Name Data SM 313 N-(2-(((6-chloro-1- ¹H NMR (400 MHz,N-[2-(amino- (tetrahydro-2H-pyran-2- DMSO-d₆): δ ppm methyl)phenyl]-N-yl)-1H-pyrazolo[3,4- 1.54 (m, 2H), 1.71 (m, 1H), methylbenzene-d]pyrimidin-4- 1.84 (m, 1H), 1.98 (m, sulfonamideyl)amino)methyl)phenyl)- 1H), 2.32 (m, 1H), hydrochloride N- 3.19 (s,3H), 3.75 (m, 1H), (Preparation 190). methylbenzenesulfonamide 3.90 (m,1H), 0.89 (br m, 1H), 5.00 (br m, 1H), 5.75 (m, 2H), 6.58 (m, 1H), 7.19(t, 1H), 7.35 (t, 1H), 7.45 (m, 1H), 7.63-7.78 (m, 5H), 8.23 (s, 1H),9.30 (m, 1H). 314 N-(2-(((6-chloro-1- MS m/z 481 [M + H]⁺N-[2-(aminomethyl)-4- (tetra-hydro-2H-pyran- ¹H NMR (400 MHz,methoxyphenyl]-N- 2-yl)-1H-pyrazolo[3,4- DMSO-d₆): δ ppm(methylsulfonyl)methanesulfonamide d]pyrimidin-4- 1.54 (m, 2H), 1.73 (m,1H), hydrochloride yl)amino)methyl)-4- 1.84 (m, 1H), 1.98 (m,(Preparation 191). methoxyphenyl)-N- 1H), 2.37 (m, 1H), methyl- 3.06 (s,3H), 3.21 (s, 3H), methanesulfonamide 3.63-3.77 (m, 4H), 3.94 (m, 1H),4.54 (m, 1H), 4.95 (m, 1H), 5.74 (m, 1H), 6.94 (m, 2H), 7.48 (m, 1H),8.22 (s, 1H), 9.22 (t, 1H). 315 N-(3-(((6-chloro-1- MS m/z 453 [M + H]⁺N-(3- (tetrahydro-2H-pyran-2- ¹H NMR (400 MHz, (aminomethyl)pyrazin-yl)-1H-pyrazolo[3,4- DMSO-d₆): δ ppm 2-yl)-N- d]pyrimidin-4- 1.54 (m,2H), 1.73 (m, 1H), methylmethanesulfonamide yl)amino)methyl)pyrazin-1.85 (m, 1H), 1.98 (m, hydrochloride 2-yl)-N-methylmethanesulfonamide1H), 2.33 (m, 1H), (WO2008/129380A1). 3.15 (s, 3H), 3.31 (s, 3H), 3.66(m, 1H), 3.90 (m, 1H), 4.90 (m, 2H), 5.73 (m, 1H), 8.24 (s, 1H), 8.54(m, 1H), 8.62 (m, 1H), 9.44 (t, 1H). 316 N-(2-(((6-(5-fluoro-2- MS m/z854 [M + H]⁺ 4-chloro-6-(5-fluoro-2- (2,2,2-trifluoroethyl)-4-(2,2,2-trifluoroethyl)-4- ((2- ((2-(trimethylsilyl)ethoxy)methoxy)phenyl)- (trimethylsilyl)ethoxy) 1-methoxy)phenyl)-1- (tetrahydro-2H-pyran-2- (tetrahydro-2H-pyran-yl)-1H-pyrazolo[3,4- 2-yl)-1H-pyrazolo[3,4- d]pyrimidin-4- d]pyrimidineyl)amino)methyl)phenyl)- (Preparation 298) N-(2-((tetrahydro-2H- andN-[2- pyran-2- (aminomethyl)- yl)oxy)ethyl)methane- phenyl]-N-[2-(tetra-sulfonamide hydro-2H-pyran-2- yloxy)ethyl]-methane- sulfonamide(Preparation 216). 317 N-(2-(((6-chloro-1- MS m/z 465 [M + H]⁺N-[2-(aminomethyl)phenyl]- (tetra-hydro-2H-pyran- N-2-yl)-1H-pyrazolo[3,4- ethylmethanesulfonamide d]pyrimidin-4-hydrochloride yl)amino)methyl)phenyl)- (Preparation 188). N-ethylmethanesulfonamide 318 N-(2-(((6-chloro-1- MS m/z 557 [M + H]⁺N-[2-(aminomethyl)-4- (tetrahydro-2H-pyran-2- methoxyphenyl]-N-yl)-1H-pyrazolo[3,4- ethylbenzenesulfonamide d]pyrimidin-4-hydrochloride yl)amino)methyl)-4- (Preparation 196). methoxyphenyl)-N-ethylbenzenesulfonamide 319 N-(2-(((6-chloro-1- MS m/z 543 [M + H]⁺N-[2-(aminomethyl)-4- (tetra-hydro-2H-pyran- methoxyphenyl]-N-2-yl)-1H-pyrazolo[3,4- methylbenzenesulfonamide d]pyrimidin-4-hydrochloride yl)amino)methyl)-4- (Preparation 195). methoxyphenyl)-N-methylbenzenesulfona 320 N-(2-(((6-chloro-1- MS m/z 469 [M + H]⁺N-[2-(aminomethyl)-4- (tetra-hydro-2H-pyran- fluorophenyl]-N-2-yl)-1H-pyrazolo[3,4- methyl- d]pyrimidin-4- methanesulfonamideyl)amino)methyl)-4- hydrochloride fluorophenyl)-N- (Preparation 186).methylmethanesulfonamide 321 benzyl (2-(((6-chloro-1- MS m/z 507 [M +H]⁺ Benzyl [2- (tetra-hydro-2H-pyran- (aminomethyl)phenyl]2-yl)-1H-pyrazolo[3,4- methylcarbamate d]pyrimidin-4- hydrochlorideyl)amino)methyl)phenyl)(methyl)carbamate (Preparation 249).

Preparation 3224-(Benzyloxy)-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidine

To a suspension of NaH (0.48 g, 20.13 mmol) in THF (50 mL) at 0° C. wasadded benzyl alcohol (1.98 g, 18.30 mol) slowly. The mixture was allowedto stir for 45 minutes at 0° C. followed by the addition of4,6-dichloro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidine(WO20131014567A1, 5 g, 18.30 mmol). The reaction was stirred at roomtemperature for 2 hours before being quenched with brine. The solutionwas extracted into EtOAc, washed with brine, dried over sodium sulfateand concentrated in vacuo. The residue was purified by silica gel columnchromatography to afford the title compound (3.4 g, 54%). ¹H NMR (400MHz, DMSO-d₆): δ ppm 1.56 (m, 2H), 1.74-1.78 (m, 1H), 1.87-1.91 (m, 1H),1.98-2.02 (m, 1H), 2.33-2.43 (m, 1H), 3.71 (m, 1H), 3.92 (m, 1H), 5.62(s, 2H), 5.86 (m, 1H), 7.38 (m, 3H), 7.55 (m, 2H), 8.37 (s, 1H). MS m/z345 [M+H]⁺

Preparation 3232-(4-(Benzyloxy)-2-ethyl-5-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

The title compound was prepared according to the method described forPreparation 150 using 1-(benzyloxy)-4-bromo-5-ethyl-2-fluorobenzene(Preparation 324). Taken on directly to the next step.

Preparation 324 1-(Benzyloxy)-4-bromo-5-ethyl-2-fluorobenzene

To a solution of 4-bromo-5-ethyl-2-fluorophenol (WO20131014567A1, 3 g,13.69 mmol) in acetone (30 mL) was added benzyl bromide (2.57 g, 15.06mmol) and the reaction heated to reflux with potassium carbonate (2.83g, 20.54 mmol) for 18 hours. The reaction was filtered, concentrated invacuo and purified using silica gel column chromatography eluting with5% EtOAc in hexanes to afford the title compound as a colorless oil(3.20 g, 76%). ¹H NMR (400 MHz, DMSO-ds): δ ppm 1.13 (t, 3H), 2.62 (q,2H), 5.18 (s, 2H), 7.26-7.51 (m, 7H).

Preparation 3252-(4-(Benzloxy)-5-fluoro-2-(2,2,2-trifluoroethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

The title compound was prepared according to the methods described forPreparations 323 and 324 using4-bromo-2-fluoro-5-(2,2,2-trifluoroethyl)phenol (Preparation 326). Takenon directly to the next step.

Preparation 326 4-Bromo-2-fluoro-5-(2,2,2-trifluoroethyl)phenol

To a solution of1-bromo-5-fluoro-4-methoxy-2-(2,2,2-trifluoroethyl)benzene(WO20131014567A1, 88.5 g, 308.31 mmol) at 0° C. in DCM (2000 mL), wasadded boron tribromide (204.56 mL, 2158.17 mmol) and the reaction wasstirred at room temperature for 18 hours. The reaction was quenched bythe addition of cold water dropwise at 0° C. The organic layer wasseparated, the aqueous extracts washed twice with DCM, the organicextracts combined, washed with brine, dried, concentrated in vacuo andtriturated with pentane to afford the title compound as a white solid(78 g, 93%). ¹H NMR (400 MHz, DMSO-d₆): δ ppm 3.66-3.74 (m, 2H), 7.10(d, 1H), 7.52 (d, 1H), 10.50 (br s, 1H).

Preparation 327N-(2-(Benzyloxy)ethyl)-N-(2-(((6-(2-ethyl-5-fluoro-4-((2-(trimethylsilyl)ethoxy)-methoxy)phenyl-1-((2-(trimethylsilyl)ethoxymethyl)-1H-pyrazolo[4,3-c]pyridin-4-yl)amino)methyl)phenyl)methanesulfonamide

A solution of6-(2-ethyl-5-fluoro-4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-c]pyridin-4-yltrifluoromethanesulfonate (Preparation 331, 100 mg, 0.15 mmol),N-(2-(aminomethyl)phenyl)-N-(2-(benzyloxy)ethyl)methanesulfonamidehydrochloride (Preparation 366, 64 mg, 0.225 mmol) and triethylamine (62μL, 0.45 mmol) in DMF (2 mL) was heated to between 80-90° C. for 36hours. The reaction was cooled and partitioned between EtOAc (50 mL) andwater (50 mL). The organic layer was collected, further washed withwater and brine, dried over sodium sulfate and concentrated in vacuo.The residue was purified using silica gel column chromatography elutingwith EtOAc in heptanes to afford the title compound (51 mg, 40%). ¹H NMR(400 MHz, CDCl₃): δ ppm 0.00 (s, 9H), 0.50 (s, 9H), 0.95 (m, 3H), 1.05(m, 3H), 1.15 (m, 3H), 2.80 (m, 2H), 3.10 (s, 3H), 3.50 (m, 1H), 3.60(m, 4H), 3.80 (m, 1H), 3.90 (m, 2H), 4.05-4.20 (m, 1H), 4.60 (m, 2H),5.15 (m, 1H), 5.20 (s, 2H), 5.60 (s, 2H), 6.15 (m, 1H), 6.80 (s, 1H),7.10-7.40 (m, 10H), 7.70 (m, 1H), 7.90 (s, 1H). MS m/z 851 [M+H]⁺

Preparation 3286-(2-Ethyl-4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-c]pyridin-4-yltrifluoromethanesulfonate

Triflic anhydride (0.21 mL, 1.25 mmol) was added dropwise to a solutionof6-(2-ethyl-4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-c]pyridin-4-ol(Preparation 329, 495 mg, 0.96 mmol) and pyridine (0.34 mL, 4.2 mmol) inDCM (5 mL) at 0° C. The reaction was stirred at room temperature for 4hours. The reaction was diluted with water (45 mL), acidified to pH=3with citric acid and extracted with EtOAc (2×45 mL). The organic layerswere combined, washed with a dilute solution of citric acid at pH=3 (45mL), saturated aqueous NaHCO₃ solution, brine, dried over sodium sulfateand concentrated in vacuo to afford the title compound that was useddirectly in the next reaction.

Preparation 3296-(2-Ethyl-4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-c]pyridin-4-ol

To a solution of6-(2-ethyl-4-((2-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-c]pyridine5-oxide (Preparation 333, 8 g, 15.5 mmol) in THF (160 mL) was added TEA(3.13 g, 31 mmol) dropwise, followed by the addition of acetic anhydride(23.7 g, 232.5 mmol) dropwise at room temperature. The reaction washeated to 65° C. for 18 hours. The reaction was cooled and quenched bythe addition of saturated aqueous NaHCO₃ solution (60 mL), and stirredfor 10 hours. The reaction was diluted with water and extracted intoEtOAc. The organic layer was collected, washed with brine, dried oversodium sulfate and concentrated in vacuo. The residue was purified usingsilica gel column chromatography to afford the title compound as an oil(5 g, 63%). ¹H NMR (400 MHz, CDCl₃): δ ppm −0.06 (s, 9H), 0.0 (s, 9H),0.84-0.88 (m, 2H), 0.94-0.98 (m, 2H), 1.12-1.16 (m, 3H), 2.62-2.64 (m,2H), 3.55-3.59 (m, 2H), 3.75-3.79 (m, 2H), 5.26 (s, 2H), 5.57 (s, 2H),6.42 (s, 1H), 6.92-6.96 (m, 1H), 6.99 (s, 1H), 7.21-7.25 (m, 1H), 8.14(s, 1H), 9.15 (s, 1H). MS m/z 516 [M+H]⁺

Preparation 3306-(2-Ethyl-5-fluoro-4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridin-4-yltrifluoromethanesulfonate

The title compound was prepared according to the methods described forPreparations 328 and 329 using6-(2-ethyl-5-fluoro-4-{[2-(trimethylsilyl)-ethoxy]methoxy}phenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine5-oxide (Preparation 332). ¹H NMR (400 MHz, DMSO-d₆): δ ppm −0.01 (s,9H), 0.91 (t, 2H), 1.04 (t, 3H), 1.59 (m, 2H), 1.71 (m, 1H), 2.30 (m,2H), 2.37 (m, 2H), 2.70 (m, 2H), 3.78 (t, 3H), 3.90 (d, 1H), 5.36 (s,2H), 6.05 (d, 1H), 7.25 (d, 1H), 7.35 (d, 1H), 8.10 (s, 1H), 8.52 (s,1H).

Preparation 3316-(2-Ethyl-5-fluoro-4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-c]pyridin-4-yltrifluoromethanesulfonate

The title compound was prepared according to the methods described forPreparations 328 and 329 using6-(2-ethyl-5-fluoro-4-((2-(trimethylsilyl)-ethoxy)methoxy)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-c]pyridine5-oxide (Preparation 335). Used directly in the next reaction.

Preparation 3326-(2-Ethyl-5-fluoro-4-{[2-(trimethylsilyl)ethoxy]methoxy}phenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine5-oxide

To a stirred solution of6-[2-ethyl-5-fluoro-4-{[2-(trimethylsilyl)-ethoxy]-methoxy}phenyl]-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine(Preparation 147, 24 g, 50.88 mmol) in anhydrous DCM (300 mL) was addedmCPBA (33.52 g, 117 mmol) and the reaction was stirred at roomtemperature for 18 hours. The reaction was quenched with saturatedaqueous NaHCO₃ solution and extracted into DCM. The organic layer wascollected, washed with brine, dried over sodium sulfate and concentratedin vacuo. The residue was purified using silica gel columnchromatography eluting with 10% heptanes in EtOAc to afford the titlecompound as a yellow solid (14.5 g, 58%). ¹H NMR (400 MHz, DMSO-d₆): δppm 0.01 (s, 9H), 0.91-0.95 (t, 2H), 1.00-1.01 (t, 3H), 1.56 (s, 2H),1.66-1.69 (m, 1H), 1.95. 1.98 (m, 2H), 2.28-2.36 (m, 3H), 3.69-3.80 (m,3H), 3.71-3.80 (m, 3H), 3.86 (d, 1H), 5.34 (s, 2H), 5.94 (d, 1H),7.16-7.23 (m, 2H), 7.94 (s, 1H), 8.20 (s, 1H), 8.91 (s, 1H). MS m/z 488[M+H]⁺

Preparation 3336-(2-Ethyl-4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-c]pyridine5-oxide

To a solution of6-(2-ethyl-4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-1-((2-(trimethylsilyl)-ethoxy)methyl)-1H-pyrazolo[4,3-c]pyridine(Preparation 336, 7 g, 14 mmol) in DCM (100 mL) was added m-CPBA (5.6 g,28 mmol) at room temperature, and the reaction was stirred for 5 hours.The reaction was washed with 10% aqueous NaHSO₃ solution and saturatedaqueous NaHCO₃ solution. The organic layer was separated, dried oversodium sulfate and concentrated in vacuo to afford the title compound (7g, 97%). ¹H NMR (400 MHz, CDCl₃): δ ppm 0.01 (s, 9H), 0.09 (s, 9H),0.92-0.96 (m, 2H), 1.03-1.07 (m, 2H), 1.17-1.21 (m, 3H), 2.41-2.56 (m,1H), 2.68-2.81 (m, 1H), 3.62-3.66 (m, 2H), 3.82-3.87 (m, 2H), 5.33 (s,2H), 5.75 (s, 2H), 6.99-7.08 (m, 1H), 7.12 (m, 1H), 7.24 (d, 1H), 7.57(d, 1H), 7.57 (d, 1H), 8.12 (s, 1H). MS m/z 516 [M+H]⁺

Preparation 3346-(5-Fluoro-4-methoxy-2-(2,2,2-trifluoroethyl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-c]pyridine5-oxide

The title compound was prepared according to the method described forPreparation 111 using6-(5-fluoro-4-methoxy-2-(2,2,2-trifluoroethyl)phenyl)-1-((2-(trimethylsilyl)ethoxy)-methyl)-1H-pyrazolo[4,3-c]pyridine(Preparation 337). MS m/z 472 [M+H]⁺

Preparation 3356-(2-Ethyl-5-fluoro-4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-c]pyridine5-oxide

The title compound was prepared according to the method described forPreparation 111 using6-(2-ethyl-5-fluoro-4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-1-((2-(trimethylsilyl)-ethoxy)methyl)-1H-pyrazolo[4,3-c]pyridine(Preparation 338). MS m/z 534 [M+H]⁺

Preparation 3366-(2-Ethyl-4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-c]pyridine

To a solution of6-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-c]pyridine

(Preparation 340, 6.7 g, 23.67 mmol) in DMSO (120 mL) was added(2-((3-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)methoxy)ethyl)trimethylsilane(Preparation 343, 9.8 g, 26.03 mmol), potassium phosphate (18.88 g,71.01 mmol) and water (12 mL) at room temperature. Pd(PPh₃)₄ (2.7 g, 2.3mmol) was added, the reaction degassed under vacuum and refilled withnitrogen, and heated to 100° C. for 18 hours. The reaction was pouredinto ice water (200 mL) and extracted with EtOAc. The organic layer waswashed with brine, dried over sodium sulfate and concentrated in vacuo.The residue was purified by silica gel column chromatography to affordthe title compound as a yellow oil (6 g, 51%). Taken on directly to thenext step.

Preparation 3376-(5-Fluoro-4-methoxy-2-(2,2,2-trifluoroethyl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-c]pyridine

The title compound was prepared according to the method described forPreparation 336 using2-[5-fluoro-4-methoxy-2-(2,2,2-trifluoroethyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(WO20131014567A1) and6-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-c]pyridine(Preparation 340). ¹H NMR (400 MHz, CDCl₃): δ ppm 0.00 (s, 9H), 0.95 (m,2H), 3.62 (m, 2H), 3.82 (q, 2H), 4.02 (s, 3H), 5.80 (s, 2H), 7.10 (m,1H), 7.30 (m, 1H), 7.60 (s, 1H), 8.25 (s, 1H), 9.12 (s, 1H).

Preparation 3386-(2-Ethyl-5-fluoro-4((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-c]pyridine

The title compound was prepared according to the method described forPreparation 336 using(2-{[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-ethylphenoxy]methoxy}ethyl)(trimethyl)-silane (WO20131014567A1) and6-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-c]pyridine(Preparation 340). ¹H NMR (400 MHz, CDCl₃): δ ppm 0.10 (s, 9H), 0.10 (s,9H), 0.93-1.00 (m, 2H), 1.04-1.08 (m, 2H), 1.13-1.22 (m, 3H), 2.76 (q,2H), 3.66 (m, 2H), 3.91 (m, 2H), 5.38 (s, 2H), 5.82 (s, 2H), 7.21-7.25(m, 2H), 7.56 (s, 1H), 8.24 (s, 1H), 9.21 (s, 1H). MS m/z 518 [M+H]⁺

Preparation 339N-(2-(((6-Chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridin-4-yl)amino)methyl)phenyl)-N-methylmethanesulfonamide

The title compound was prepared according to the method described forPreparation 312 using4,6-dichloro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine(Preparation 341) andN-[2-(aminomethyl)phenyl]-N-methylmethane-sulfonamide (WO20101058846A1).¹H NMR (400 MHz, DMSO-d₆): δ ppm 1.55 (m, 2H), 1.69 (m, 1H), 1.88-2.00(m, 2H), 2.29 (m, 1H), 3.04 (s, 1H), 3.27 (s, 3H), 3.69 (m, 1H), 3.85(m, 1H), 4.55 (br m, 1H), 4.91 (br m, 1H), 5.67 (m, 1H), 6.91 (s, 1H),7.32-7.52 (m, 4H), 8.24 (s, 1H), 8.29 (t, 1H). MS m/z 449 [M+H]⁺

Preparation 3406-Chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-c]pyridine

To a solution of 6-chloro-1H-pyrazolo[4,3-c]pyridine (8.5 g, 55 mmol) inanhydrous THF (200 mL) was added NaH (60% dispersion in oil, 2.3 g, 58mmol) at 0° C. After stirring at room temperature for 20 minutes, SEMCl(9.67 g, 58.06 mmol) was added dropwise at 0° C. The reaction wasstirred at room temperature for 2 hours before quenching with water andextracting into EtOAc. The organic layer was separated, dried overNa₂SO₄ and concentrated in vacuo. The residue was purified by silica gelcolumn chromatography to afford the title compound as a yellow oil (14g, 90%). Taken on directly to the next step.

Preparation 3414,6-Dichloro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine

The title compound was prepared according to the method described forPreparation 149 using 4,6-dichloro-1H-pyrazolo[4,3-c]pyridine. ¹H NMR(400 MHz, DMSO-d₆): δ ppm 1.58-1.61 (m, 3H), 1.97-2.03 (m, 2H),2.31-2.34 (m, 1H), 3.76-3.80 (s, 1H), 3.84-3.91 (m, 1H), 5.92-5.95 (d,1H), 8.07 (s, 1H), 8.46 (s, 1H). MS m/z 272 [M+H]⁺

Preparation 3422-((4-Benzyloxy)-2-ethyl-6-methylphenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

To a solution of 3-ethyl-4-iodo-5-methylphenol (J. Med. Chem. (2005),48(2), 586-592, 500 mg, 1.90 mmol) in acetone (20 mL) was addedbenzylbromide (1.43 mL, 2.86 mmol) and potassium carbonate (658 mg, 4.77mol). The reaction was heated to 70° C. for 18 hours. The reaction wascooled, filtered and concentrated in vacuo. The residue was dissolved inEtOAc and washed with water, brine, dried over sodium sulfate andconcentrated in vacuo. The residue was purified by silica gel columnchromatography eluting with hexanes. The residue was dissolved inanhydrous DMSO (1.6 mL) and bis(pinacolonato)diboron (1032 mg, 4.06mmol) and KOAc (543 mg, 5.54 mmol) were added The reaction was purgedunder argon for 10 minutes before the addition of Pd(dppf)₂Cl₂ (135 mg,0.18 mmol) followed by degassing for another 10 minutes and then heatingto 80° C. for 18 hours. The reaction was cooled, concentrated in vacuoand suspended in EtOAc. The suspension was filtered through celite andthe filtrate washed with water, dried over sodium sulfate andconcentrated in vacuo. The residue was purified using silica gel columnchromatography eluting with 5% EtOAc in hexanes to afford the titlecompound. ¹H NMR (400 MHz, DMSO-d₆): δ ppm 1.10 (t, 3H), 1.30 (s, 12H),2.28 (s, 3H), 2.60 (q, 2H), 5.06 (s, 2H), 6.63 (m, 2H), 7.31-7.44 (m,5H).

Preparation 343(2-((3-Ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)methoxy)ethyl)trimethylsilane

To a solution of(2-((4-bromo-3-ethylphenoxy)methoxy)ethyl)trimethylsilane (Preparation344, 300 mg, 0.9 mmol) in dioxane (5 mL) was added bispinacolatodiboron(276 mg, 1.09 mmol), Pd(PPh₃)₄ (105 mg, 0.09 mmol) and potassiumphosphate (384 mg, 1.81 mmol) and the reaction was heated to 80° C. for18 hours. The reaction was cooled and partitioned between water andEtOAc, eluted though a phase separation cartridge and concentrated invacuo. The residue was purified using silica gel column chromatographyeluting with 0-50% DCM in heptanes to afford the title compound. Takenon directly to the next step.

Preparation 344(2-((4-Bromo-3-ethylphenoxy)methoxy)ethyl)trimethylsilane

To a solution of 4-bromo-3-ethylphenol (9 g, 44.8 mmol) in DCM (100 mL)was added DIPEA (8.6 mL, 49.3 mmol) followed by SEMCl (8.73 mL, 49.3mmol) and the reaction was stirred at room temperature for 18 hours. Thereaction was washed with water, 1N aqueous HCl solution and saturatedaqueous sodium hydrogen carbonate solution, brine, dried over sodiumsulfate and concentrated in vacuo. The residue was purified using silicagel column chromatography eluting with 3% EtOAc in hexanes to afford thetitle compound. ¹H NMR (400 MHz, CDCl₃): δ ppm 0.00 (s, 9H), 0.90 (m,2H), 1.25 (m, 3H), 2.75 (m, 2H), 3.75 (m, 2H), 5.20 (s, 2H), 6.80 (m,1H), 7.00 (d, 1H), 7.40 (d, 1H).

Preparation 3456-(4-Methyl-1H-imidazol-1-yl)-1,2,3,4-tetrahydroisoquinolinehydrochloride

To a solution of 6-fluoro-3,4-dihydro-2H-isoquinolin-1-one (13 g, 79mmol) in DMSO (150 mL) was added 4-methylimidazole (7.8 g, 95 mmol)followed by cesium carbonate (38 g, 118.5 mmol) and the reaction washeated to 125° C. for 18 hours. The reaction was cooled and extractedinto chloroform/isopropanol (v:v 3:1, 500 mL) three times. The organiclayers were combined, washed with brine, dried over sodium sulfate andconcentrated in vacuo. A portion of the residue (9 g, 39.6 mmol) wasdissolved in THF and cooled to 0° C. LiAlH₄ (3 g, 79.2 mmol) was addedportionwise, and the reaction heated to 60° C. for 18 hours. Thereaction was cooled and quenched by the addition of 10% NaOH solution (6mL), before filtration and concentration in vacuo. The residue waspurified by silica gel column chromatography eluting with 30-100% EtOAcin petroleum ether followed by the addition of 2N HCl in EtOAc. Theresulting precipitate was filtered to afford the title compound as thehydrochloride salt (11.6 g, 42%). ¹H NMR (400 MHz, DMSO-d₆): δ ppm 2.34(s, 3H), 3.08 (m, 2H), 3.37 (m, 2H), 4.30 (m, 2H), 7.48 (m, 1H),7.62-7.68 (m, 2H), 8.00 (s, 1H), 9.61 (s, 1H), 9.91 (br s, 2H).

Preparation 346N-(2-(Pyrrolidin-1-yl)ethyl)-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide

To a solution of1,2,3,4-tetrahydro-2-(2,2,2-trufluoroacetyl)-7-isoquinoline sulfonylchloride (400 mg, 1.2 mmol) in MeOH (5 mL) was added2-(pyrrolidin-1-yl)ethanamine in excess and the reaction stirred at roomtemperature for 30 minutes. Water (1 mL) followed by potassium carbonate(150 mg, 1.4 mmol) were added and the reaction stirred at roomtemperature for 18 hours. The reaction was concentrated in vacuo and theresidue dissolved in DCM. The suspension was filtered and the filtratepurified by silica gel column chromatography eluting with 10-100%(90:10:1 DCM:MeOH:NH₃) in DCM to afford the title compound (130 mg,35%). MS m/z 310 [M+H]⁺

Preparation 347 N-Benzyl-1,2,3,4-tetrahydroisoquinoline-5-carboxamidehydrochloride

To a solution of2-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinoline-5-carboxylic acid(200 mg, 0.721 mmol) and DIPEA (87 μL, 0.793 mmol) in DCM (10 mL) wasadded HBTU (301 mg, 0.793 mmol) followed by a solution of benzylamine(151 μL 0.865 mmol) in DCM (5 mL) and the reaction was stirred at roomtemperature for 72 hours. The reaction was washed with water (1 mL), 1NHCl (aq) (1 mL) and 1N NaOH (aq) (1 mL). The organic layer was driedover sodium sulfate and concentrated in vacuo. The residue was dissolvedin MeOH (5 mL) and 4N HCl in dioxane (3 mL) was added. The reaction wasstirred at room temperature for 18 hours. The reaction was concentratedin vacuo and triturated with diethylether to afford the title compoundas the hydrochloride salt (200 mg, quant.).

¹H NMR (400 MHz, DMSO-d₆): δ ppm 3.09 (t, 2H), 3.33 (m, 2H), 4.28 (t,2H), 4.44 (d, 2H), 5.19 (s, 2H), 5.95 (d, 1H), 7.23-7.42 (m, 8H), 8.93(t, 1H), 9.49 (br s, 2H).

Preparation 348 3-(Azetidin-3-yloxy)-4-chlorobenzonitrile hydrochloride

To a solution of 1-benzhydryl-3-azetidinyl methanesulfonate (44.6 g,0.147 mol) and 2-chloro-5-cyanophenol (22.6 g, 0.147 mol) in MeCN (600mL) was added Cs₂CO₃ (62.3 g, 0.19 mol). The reaction was stirred at 80°C. for 24 hours. The reaction was filtered, and the filtrate wasconcentrated in vacuo. The residue was purified by silica gel columnchromatography eluting with 5-20% EtOAc in petroleum ether. The residuewas dissolved in dichloroethane (550 mL) and potassium carbonate (66.4g, 0.48 mmol) followed by ACE-Cl (20.5 g, 0.14 mmol) was added. Thereaction was heated to reflux for 2 hours. The reaction was concentratedin vacuo and the residue was recrystallized with MeOH to afford thetitle compound as the hydrochloride salt (13.8 g, 59%). ¹H NMR (400 MHz,MeOD): δ ppm 4.21-4.25 (m, 2H), 4.61-4.66 (m, 2H), 5.25-5.31 (m, 1H),7.30 (s, 1H), 7.40-7.43 (d, 1H), 7.63-7.65 (d, 1H).

Preparation 349 N-(2-(Aminomethyl)phenyl)-N-propylmethanesulfonamidetrifluoroacetate

To a solution of tert-butyl 2-(N-propylmethylsulfonamido)benzylcarbamate(Preparation 351, 265 mg, 0.77 mmol) in DCM (2 mL) was added TFA (0.5mL) and the reaction stirred at room temperature for 1 hour. Thereaction was diluted with DCM and washed with a 1:1 mixture of 880 NH₃in water (20 mL). The organic layer was collected, dried over magnesiumsulfate and concentrated in vacuo to afford the title compound as thetrifluoroacetate salt (172 mg, 92%). ¹H NMR (400 MHz, CDCl₃): δ ppm 0.89(t, 3H), 1.41-1.55 (m, 2H), 2.96 (s, 3H), 3.39-3.46 (m, 1H), 3.62-3.69(m, 1H), 3.83-3.87 (m, 1H), 4.10-4.20 (m, 1H), 7.19-7.22 (m, 1H),7.28-7.32 (m, 1H), 7.36-7.40 (m, 1H), 7.57 (d, 1H).

Preparation 350 N-(2-(Aminomethyl)phenyl)-N-butylmethanesulfonamidetrifluoroacetate

The title compound was prepared according to the method described byPreparation 349 using tert-butyl2-(N-butylmethylsulfonamido)benzylcarbamate (Preparation 354) andisolated as the trifluoroacetate salt. ¹H NMR (400 MHz, CDCl₃): δ ppm0.87 (t, 3H), 1.26-1.52 (m, 4H), 2.95 (s, 3H), 3.41-3.48 (m, 1H),3.67-3.75 (m, 1H), 3.83-3.86 (m, 1H), 4.10-4.14 (m, 1H), 7.19-7.21 (m,1H), 7.28-7.32 (m, 1H), 7.37-7.41 (m, 1H), 7.58 (d, 1H).

Preparation 351 tert-Butyl 2-(N-propylmethylsulfonamido)benzylcarbamate

The title compound was prepared according to the method described byPreparation 213 using N-(2-cyanophenyl)-N-propylmethanesulfonamide(Preparation 352). Taken on directly to the next step.

Preparation 352 N-(2-Cyanophenyl)-N-propylmethanesulfonamide

To a solution of N-(2-cyanophenyl)methanesulfonamide (Preparation 223,500 mg, 2.55 mmol) in NMP (10 mL) was added sodium hydride (148 mg, 3.83mmol) and the reaction stirred for 30 minutes at room temperature.Propyl iodide (1.74 mL, 3.83 mmol) was added and the reaction wasstirred at room temperature for 18 hours. The reaction was quenched bythe addition of water and extracted into EtOAc. The organic layer wascollected, washed with water, dried over sodium sulfate and concentratedin vacuo. The residue was purified using silica gel columnchromatography eluting with 30% EtOAc in heptanes to afford the titlecompound (505 mg, 83%). ¹H NMR (400 MHz, CDCl₃): δ ppm 0.94 (t, 3H),1.48-1.60 (m, 2H), 3.11 (s, 3H), 3.71 (t, 2H), 7.46-7.54 (m, 2H),7.65-7.69 (m, 1H), 7.72-7.74 (m, 1H).

Preparation 353N-Methyl-N-(2-(((2-morpholinoethyl)amino)methyl)phenyl)methanesulfonamide

Sodium hydride (76 mg, 1.92 mmol) was added to a solution of tert-butyl2-(N-methylmethylsulfonamido)benzylcarbamate (WO20101058846A1, 200 mg,0.64 mmol) in NMP and the reaction was stirred at 0° C. for 30 minutes.2-morpholinoethanamine (226 mg, 0.96 mL) was added and the reactionstirred at room temperature for 18 hours. The reaction was quenched bythe addition of water and extracted into EtOAc. The organic layer wascollected, dried and concentrated in vacuo. The residue was purifiedusing silica gel column chromatography eluting with 100:10:1DCM:MeOH:TEA. The residue was dissolved in DCM (2 mL) and TFA (1 mL) wasadded. The reaction was stirred at room temperature for 1 hour. Thereaction was concentrated in vacuo to afford the title compound as thetrifluoroacetate salt. MS m/z 328 [M+H]⁺

The following Preparations (Preparations 354-359) were preparedaccording to the method described by Preparation 353 using theappropriate sulphonamide and alkyl halide as described below. Thecompounds were isolated according to the described experimental or bydissolving in DCM (20 mL) and washing with a 1:1 mixture of ammoniumhydroxide:water. The organic layer was collected, dried over magnesiumsulfate and concentrated in vacuo to afford the title compound that wasused in the next reaction directly.

Preparation Number Name SM Data 354 N-butyl-N-(2- tert-butyl 2-(N- ¹HNMR (400 MHz, ((methyl- butylmethylsulfonamido)benzylcarbamate CDCl₃): δppm 0.88 (t, amino)methyl)phenyl)methanesulfonamide (Preparation 3H),1.27-1.58 (m, 4H), 364) and methyl iodide. 2.50 (s, 3H), 2.95 (s, 3H),3.44-3.50 (m, 1H), 3.67-3.76 (m, 2H), 3.95-4.00 (m, 1H), 7.20-7.23 (m,1H), 7.28-7.32 (m, 1H), 7.34-7.38 (m, 1H), 7.61 (d, 1H). 355N-ethyl-N-(4- tert-butyl 2-(N- Taken on directly to the methyl-2-ethylmethylsulfonamido)-5- next step.((methylamino)methyl)phenyl)methanesulfonamide methylbenzylcarbamate(Preparation 361) and methyl iodide. 356 N-(2- tert-butyl 5-methyl-2-(N-¹H NMR (400 MHz, ((ethylamino)methyl)-methylmethylsulfonamido)benzylcarbamate CDCl₃): δ ppm 1.21 (t, 4-(Preparation 360) and ethyl 3H), 2.32 (s, 3H), methylphenyl)N- iodide.2.82 (m, 2H), 2.99 (s, 3H), methylmethanesulfonamide 3.21 (s, 3H), 3.95(s, 2H), 7.07 (m, 2H), 7.40 (s, 1H). 357 N-methyl-N-(4- tert-butyl5-methyl-2-(N- ¹H NMR (400 MHz, methyl-2-methylmethylsulfonamido)benzylcarbamate CDCl₃): δ ppm 0.95 (t, ((propyl-(Preparation 360) and 3H), 1.60 (q, 2H), 2.83 (d,amino)methyl)phenyl)methanesulfonamide propyl iodide. 3H), 2.31 (s, 3H),2.95 (s, 3H), 3.20 (s, 3H), 3.95 (s, 2H), 7.07 (m, 2H), 7.40 (s, 1H).358 N-ethyl-N-(2- tert-butyl 2-(N- Taken on directly to the((methylamino)methyl)phenyl)methanesulfonamideethylmethylsulfonamido)benzylcarbamate next step. (Preparation 362) andmethyl iodide. 359 N-methyl-N-(2- tert-butyl 2-(N- Taken on directly tothe ((methylamino)methyl)phenyl)methanesulfonamidemethylmethylsulfonamido)benzylcarbamate next step. (Preparation 363) andmethyl iodide.

The following Preparations (Preparations 360-364) were preparedaccording to the methods described by Preparations 351 and 352 using theappropriate sulphonamide and alkyl halide as described below:

Preparation Number Name SM Data 360 tert-butyl 5- N-(2-cyano-4- Taken ondirectly to methyl-2-(N- methylphenyl)- the next step.methylmethylsulfonamido)benzylcarbamate methanesulfonamide (Preparation365) and methyl iodide. 361 tert-butyl 2-(N- N-(2-cyano-4- MS m/z 343[M + H]⁺ ethyl- methylphenyl)- Taken on directly to methylsulfonamido)-methanesulfonamide the next step. 5- (Preparation 365) andmethylbenzylcarbamate ethyl iodide. 362 tert-butyl 2-(N-N-(2-cyanophenyl)methanesulfonamide MS m/z 329 [M + H]⁺ ethyl-(Preparation 223) and Taken on directly tomethylsulfonamido)benzylcarbamate ethyl iodide. the next step. 363tert-butyl 2-(N- N-(2- MS m/z 315methylmethylsulfonamido)benzylcarbamate cyanophenyl)methanesulfonamide[M + H]⁺Taken on (Preparation 223) directly to the next and methyliodide step. 364 tert-butyl 2-(N- N-(2- ¹H NMR (400 MHz,butylmethylsulfonamido)benzylcarbamate cyanophenyl)methanesulfonamideCDCl₃): δ ppm 0.87 (t, (Preparation 223) 3H), 1.26-1.55 (m, and butyliodide 13H), 2.94 (s, 3H), 3.39-3.46 (m, 1H), 3.71-3.78 (m, 1H),4.30-4.35 (m, 1H), 4.56-4.61 (m, 1H), 5.35 (br s, 1H), 7.19-7.21)m, 1H),7.30-7.39 (m, 2H), 7.60 (d, 1H).

Preparation 365 N-(2-Cyano-4-methylphenyl)methanesulfonamide

The title compound was prepared according to the method described forPreparation 223 using methyl iodide andN-(4-methyl-2-cyanophenyl)-N-(methylsulfonyl)methanesulfonamide(Preparation 242). Taken on directly to the next step.

Preparation 366N-(2-(Aminomethyl)phenyl)-N-(2-(benzloxy)ethyl)methanesulfonamidehydrochloride

The title compound was prepared according to the methods described forPreparations 222, 213 and 211 using 2-(benzyloxy)ethanol andN-(2-cyanophenyl)methanesulfonamide. MS m/z 335 [M+H]⁺

Preparation 367N-(2-(((3,4-Dimethoxyphenethyl)amino)methyl)phenyl)-N-methylmethanesulfonamide

To a solution of2-(3,4-dimethoxyphenyl)-N-(2-(N-methylmethylsulfonamido)benzyl)acetamide(Preparation 368, 800 mg, 2.03 mmol) in THF (15 mL) was addedborane-dimethylsulfide (2M in THF, 2.55 mL, 5.10 mmol) and the reactionwas heated to reflux for 2.5 hours. The reaction was cooled,concentrated in vacuo and the residue dissolved in methanol (12 mL). Thesolution was treated with 6N HCl (8 mL) and heated to reflux for 2hours. The reaction was concentrated in vacuo and the residue basifiedwith 3N NaOH solution. The aqueous layer was extracted into 10%MeOH/DCM, the organic extracts were washed with brine, dried over sodiumsulfate and concentrated in vacuo. The residue was purified using silicagel column chromatography eluting with 7% MeOH in DCM to afford thetitle compound (390 mg, 51%). ¹H NMR (400 MHz, DMSO-d₆): δ ppm 2.63-2.71(m, 4H), 3.04 (s, 3H), 3.17 (s, 3H), 3.71 (s, 6H), 3.80 (br s, 2H),6.68-6.83 (m, 3H), 7.28-7.51 (m, 4H). MS m/z 379 [M+H]⁺

Preparation 3682-(3,4-Dimethoxyphenyl)-N-(2-(N-methylmethylsulfonamido)benzyl)acetamide

To a solution of N-[2-(aminomethyl)phenyl]-N-methylmethanesulfonamide(WO 2010/058846A1, 1 g, 3.64 mmol) and 2-(3,4-dimethoxyphenyl)aceticacid (786 mg, 4.00 mmol) in THF (20 mL) was added propylphosphonicanhydride (2.9 g, 9.11 mmol) followed by DIPEA (2.21 mL, 12.68 mmol) andthe reaction was stirred at room temperature for 14 hours. The reactionwas concentrated in vacuo and the residue was partitioned between EtOAcand saturated aqueous sodium bicarbonate solution. The organic layer wascollected, washed with brine, dried, concentrated in vacuo and purifiedusing silica gel column chromatography eluting with 4% MeOH in DCM toafford the title compound as a white solid (540 mg, 38%). ¹H NMR (400MHz, DMSO-d₆): δ ppm 3.05 (s, 3H), 3.14 (s, 3H), 3.40 (s, 2H), 3.71 (s,6H), 4.26 (br s, 1H), 4.46 (br s, 1H), 6.77-6.88 (m, 3H), 7.26-7.34 (m,3H), 7.45-7.47 (m, 1H), 8.34 (t, 1H). MS m/z 393 [M+H]⁺

Preparation 369N-Methyl-N-(2-(((4-(methylsulfonamido)phenethyl)amino)methyl)phenyl)methanesulfonamide

The title compound was prepared according to the methods described forPreparations 368 and 367 using 2-(4-(methylsulfonamido)phenyl)aceticacid. ¹H NMR (400 MHz, DMSO-d₆): δ ppm 2.66-2.73 (m, 4H), 2.92 (s, 3H),3.04 (s, 3H), 3.13 (s, 3H), 3.80 (br s, 2H), 7.09-7.17 (m, 4H),7.29-7.34 (m, 2H), 7.42-7.49 (m, 2H), 9.52 (br s, 1H). MS m/z 412 [M+H]⁺

Preparation 370N-(2-(((6-(5-Fluoro-4-methoxy-2-(2,2,2-trifluoroethyl)phenyl)-3-(4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)methyl)-4-methoxyphenyl)-N-methylmethanesulfonamide

The title compound was prepared according to the method described forExample 157 usingN-(2-(((6-(5-fluoro-4-methoxy-2-(2,2,2-trifluoroethyl)phenyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)methyl)-4-methoxyphenyl)-N-methylmethanesulfonamide(Preparation 273) and tert-butyl2-iodo-6,7-dihydro-1H-imidazo[4,5-c]pyridine-5(4H)-carboxylate(WO20131014567A1) using HCl in dioxane for the deprotection step. MS m/z690 [M+H]⁺

Preparation 371N-(2-(((6-(5-Fluoro-4-methoxy-2-(2,2,2-trifluoroethyl)phenyl)-3-(5-(piperidin-4-yl)-4H-1,2,4-triazol-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)methyl)-4-methoxyphenyl)-N-methylmethanesulfonamide

To a solution ofN-(2-(((6-(5-fluoro-4-methoxy-2-(2,2,2-trifluoroethyl)phenyl)-3-(hydrazinecarbonyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)methyl)-4-methoxyphenyl)-N-methylmethanesulfonamide(Preparation 375, 450 mg, 0.59 mol) in butanol (2 mL) was addedtert-butyl 4-cyanopiperidine-1-carboxylate (624 mg, 2.97 mmol) and thereaction was heated to 150° C. under microwave irradiation for 50minutes. The reaction was cooled, filtered and concentrated in vacuo.The residue was purified using preparative HPLC. The residue was treatedwith TFA (2 mL) and stirred at room temperature for 30 minutes. Thereaction was concentrated in vacuo, dissolved in MeOH (5 mL) and cooledin ice water. Ethylene diamine was added dropwise until the solution wasbasic, with stirring for 1 hour. The solution was concentrated in vacuoand extracted into 20% IPA in DCM. The organic layer was washed withwater, dried over sodium sulfate and concentrated in vacuo to afford thetitle compound that was used directly in the next reaction. MS m/z 719[M+H]⁺

Preparation 372N-(2-(((6-(5-Fluoro-4-methoxy-2-(2,2,2-trifluoroethyl)phenyl)-3-(5-(piperidin-4-yl)-4H-1,2,4-triazol-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)methyl)phenyl)-N-methylmethanesulfonamide

The title compound was prepared according to the method described byPreparation 371 usingN-(2-(((3-cyano-6-(5-fluoro-4-methoxy-2-(2,2,2-trifluoro-ethyl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)methyl)phenyl)-N-methylmethanesulfonamide(Preparation 377) and tert-butyl4-(hydrazinecarbonyl)piperidine-1-carboxylate in the presence ofpotassium carbonate. MS m/z 689 [M+H]⁺

Preparation 3736-[5-Fluoro-2-ethyl-4-{[2-(trimethylsilyl)ethoxy]methoxyphenyl]-4-(2-[methyl(methylsulfonyl)amino]benzyl}amino)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazolo[4,3-c]pyridine-3-carboxylicacid

The title compound may be prepared according to the method described forPreparation 11 usingN-[2-({[6-(2-ethyl-5-fluoro-4-{[2-(trimethylsilyl)ethoxy]meth-oxy}phenyl)-3-iodo-1-{[2-(trimethylsilyl)-ethoxy]methyl}-1H-pyrazolo[4,3-c]pyridin-4-yl]-amino}methyl)phenyl]-N-methylmethanesulfonamide(Preparation 79). Taken on directly to the next step.

Preparation 374N-(2-(((6-(5-Fluoro-2-(2,2,2-trifluoroethyl)-4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-3-(hydrazinecarbonyl)-1-((2-(trimethylsilyl)ethoxy)methyl-1H-pyrazolo[4,3-c]pyridin-4-yl)amino)methyl)phenyl)-N-methylmethanesulfonamide

To a solution of6-[5-fluoro-2-(2,2,2-trifluoroethyl)-4-{[2-(trimethylsilyl)ethoxy]methoxy}phenyl]-4-({2-[methyl(methylsulfonyl)amino]benzyl}amino)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazolo[4,3-c]pyridine-3-carboxylicacid (Preparation 12, 0.55 g, 0.66 mmol) in MeOH/Toluene (15 mL) wasadded 2M trimethylsilyldiazomethane in THF (0.997 mL, 1.99 mmol)dropwise at 0° C. The reaction was stirred for 2 hours at roomtemperature. The reaction was concentrated in vacuo and the residue waspurified using silica gel column chromatography eluting with 8% MeOH inDCM. The residue was dissolved in MeOH (5 mL) and hydrazine monohydrate(40.12 mg, 0.80 mmol) was added. The reaction was heated to reflux for18 hours. The reaction was concentrated in vacuo and the residue waspurified using neutral alumina column chromatography eluting with 50%EtOAc in hexanes to afford the title compound (297 mg, 66%). MS m/z 842[M+H]⁺

Preparation 375N-(2-(((6-(5-Fluoro-4-methoxy-2-(2,2,2-trifluoroethyl)phenyl)-3-(hydrazinecarbonyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)methyl)-4-methoxyphenyl)-N-methylmethanesulfonamide

The title compound was prepared according to the method described byPreparation 374 using6-(5-fluoro-4-methoxy-2-(2,2,2-trifluoroethyl)phenyl)-4-((5-methoxy-2-(N-methylmethylsulfonamido)benzyl)amino)-1-((2-(trimethylsilyl)ethoxy)-methyl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylicacid (Preparation 269). MS m/z 757 [M+H]⁺

Preparation 376N-(2-(((6-(5-Fluoro-4-methoxy-2-(2,2,2-trifluoroethyl)phenyl)-3-(hydrazinocarbonyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-c]pyridin-4-yl)amino)methyl)phenyl)-N-methylmethanesulfonamide

The - was prepared according to the methods described for Preparations11 and 374 usingN-(2-(((6-(5-fluoro-4-methoxy-2-(2,2,2-tri-fluoroethyl)phenyl)-3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-c]pyridin-4-yl)amino)methyl)phenyl)-N-methyl-methanesulfonamide(Preparation 378). ¹H NMR (400 MHz, DMSO-d₆): δ ppm −0.11 (s, 9H), 0.83(m, 2H), 1.23 (br s, 2H), 3.05 (s, 3H), 3.11 (s, 3H), 3.57 (m, 2H), 3.77(m, 2H), 3.86 (s, 3H), 4.68 (m, 2H), 4.80 (br m, 1H), 4.90 (br m, 1H),5.72 (s, 2H), 7.08 (s, 1H), 7.20-7.51 (m, 6H), 9.68 (t, 1H), 10.17 (m,1H). MS m/z 726 [M+H]⁺

Preparation 377N-(2-(((3-Cyano-6-(5-fluoro-4-methoxy-2-(2,2,2-trifluoroethyl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)methyl)phenyl)-N-methylmethanesulfonamide

To a solution ofN-(2-(((6-(5-fluoro-4-methoxy-2-(2,2,2-trifluoroethyl)phenyl)-3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-c]pyridin-4-yl)amino)methyl)-phenyl)-N-methylmethanesulfonamide(Preparation 378, 1.2 g, 1.51 mmol) in DMF (10 mL), was added zinccyanide (0.19 g, 1.66 mmol) and Pd(PPh₃)₄ (0.05 mg, 0.04 mmol). Thereaction was degassed with nitrogen and heated to 120° C. undermicrowave irradiation for 20 minutes. The reaction was quenched withwater and extracted into ethyl acetate. The organic extracts were driedover sodium sulfate and concentrated in vacuo. The residue was purifiedby silica gel column chromatography eluting with 48% EtOAc in hexanes toafford the title compound (610 mg, 58%). ¹H NMR (400 MHz, DMSO-d₆): 5ppm −0.07 (s, 9H), 0.86 (t, 2H), 3.08 (s, 3H), 3.17 (s, 3H), 3.65 (t,2H), 3.88 (s, 3H), 4.22 (m, 2H), 4.89 (br m, 1H), 5.00 (br m, 1H), 5.75(s, 2H), 7.24-7.41 (m, 4H), 7.55-7.59 (m, 2H), 8.29 (t, 1H). MS m/z 694[M+H]⁺

Preparation 378N-(2-(((6-(5-Fluoro-4-methoxy-2-(2,2,2-trifluoroethyl)phenyl)-3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-c]pyridin-4-yl)amino)methyl)phenyl)-N-methylmethanesulfonamide

The title compound was prepared according to the method described forPreparation 61 using6-[5-fluoro-4-methoxy-2-(2,2,2-trifluoroethyl)phenyl]-3-iodo-1-{([2-(trimethylsilyl)ethoxy]-methyl}-1H-pyrazolo[4,3-c]pyridine(Preparation 111) and 4-nitrophenyl{2-[methyl(methylsulfonyl)amino]benzyl}carbamate (Preparation 166). MSm/z 794 [M+H]⁺

Preparation 3796-(5-Fluoro-2-(2,2,2-trifluoroethyl)-4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-3-iodo-N-(2-(methylthio)ethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-c]pyridin-4-amine

The title compound was prepared according to the method described forPreparation 61 using6-[5-fluoro-2-(2,2,2-trifluoroethyl)-4-{[2-(trimethylsilyl)ethoxy]methoxy}phenyl]-3-iodo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazolo[4,3-c]pyridine5-oxide (Preparation 114) and 4-nitrophenyl(2-(methylthio)ethyl)carbamate (Preparation 385). MS m/z 787 [M+H]⁺

Preparation 380 Racemic3-((6-(5-Fluoro-2-(2,2,2-trifluoroethyl)-4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)-2-methylpropan-1-ol

The title compound was prepared according to the method described forPreparation 131 using racemicN-(3-((tert-butyldimethylsilyl)oxy)-2-methylpropyl)-6-(4-((tert-butyldimethylsilyl)-oxy)-5-fluoro-2-(2,2,2-trifluoroethyl)phenyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine(Preparation 381). MS m/z 786 [M+H]⁺

Preparation 381 RacemicN-(3-((tert-Butyldimethylsilyl)oxy)-2-methylpropyl)-6-(4-((tert-butyldimethylsilyl)oxy)-5-fluoro-2-(2,2,2-ethyl)phenyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine

The title compound was prepared according to the method described forPreparation 137 using racemicN-(3-((tert-butyldimethylsilyl)oxy)-2-methylpropyl)-6-(4-((tert-butyldimethylsilyl)oxy)-5-fluoro-2-(2,2,2-trifluoroethyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine(Preparation 382). ¹H NMR (400 MHz, DMSO-d₆): δ ppm −0.01 (s, 6H), 0.22(s, 6H), 0.79 (m, 9H), 0.98 (m, 12H), 2.04 (m, 1H), 3.48 (m, 1H), 3.56(m, 2H), 3.68 (m, 1H), 4.45 (m, 2H), 6.71 (m, 1H), 7.13 (m, 1H), 7.81(m, 1H), 13.88 (s, 1H). MS m/z 754 [M+H]⁺

Preparation 382 RacemicN-(3-((tert-Butyldimethylsilyl)oxy)-2-methylpropyl)-6-(4-((tert-butyldimethylsilyl)oxy)-5-fluoro-2-trifluoroethyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine

The title compound was prepared according to the methods described byPreparations 142 and 141 using racemic3-((6-(5-fluoro-2-(2,2,2-trifluoroethyl)-4-((2-(trimethylsilyl)-ethoxy)methoxy)phenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)-2-methylpropan-1-ol(Preparation 383). MS m/z 626 [M−H]−

Preparation 383 Racemic3-((6-(5-Fluoro-2-(2,2,2-trifluoroethyl-4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)-2-methylpropan-1-ol

The title compound was prepared according to the method described forPreparation 299 using racemic3-((6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)-2-methylprop-an-1-ol(Preparation 384) and(2-{[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(2,2,2-trifluoroethyl)phenoxy]-methoxy}ethyl)(trimethyl)silane (Preparation 150). MS m/z 614 [M+H]⁺

Preparation 384 Racemic3-((6-Chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-dlo]pyrimidin-4-yl)amino)-2-methylpropan-1-ol

The title compound was prepared according to the method described byPreparation 299 using racemic 3-amino-2-methylpropan-1-ol. MS m/z 326[M+H]⁺

Preparation 385 4-Nitrophenyl (2-(methylthio)ethyl)carbamate

The title compound was prepared according to the method described forPreparation 156 using 2-(methylthio)ethanamine. Taken on directly to thenext step.

Preparation 3862-Bromo-4,5-dimethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole

To solution of4,5-dimethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole(Preparation 387, 270 mg, 1.19 mmol) in anhydrous THF (3 mL) at −78° C.,was added butyllithium (0.54 mL, 1.31 mmol) dropwise. The reaction waskept at −78° C. for 15 minutes before the addition of carbontetrabromide (474 mg, 1.43 mmol) in THF (2 mL). The reaction was warmedto room temperature before quenching with ammonium chloride andextracting into EtOAc. The organic layer was collected, washed withwater, brine, dried over sodium sulfate and concentrated in vacuo. Theresidue was purified by silica gel column chromatography eluting with 3%MeOH in DCM to afford the title compound as a colorless oil (220 mg,60%). ¹H NMR (400 MHz, DMSO-d₆): δ ppm −0.01 (s, 9H), 0.87 (t, 2H), 2.01(s, 3H), 2.14 (s, 3H), 3.51 (t, 2H), 5.18 (s, 2H).

Preparation 3874,5-Dimethyl-1-((2-(trimethylsilyl)ethoxymethyl)-1H-imidazole

A suspension of NaH (124 mg, 3.12 mmol) in DMF (3 mL) was added asolution of 4,5-dimethyl-1H-imidazole (200 mg, 2.08 mmol) in DMF (2 mL)at 0° C. The suspension was stirred for 15 minutes before the dropwiseaddition of SEM chloride (0.44 mL, 2.49 mmol). The reaction was stirredat room temperature for 1 hour, then partitioned between ethyl acetateand water. The combined organic extracts were washed with brine, driedover sodium sulfate and concentrated in vacuo. The residue was purifiedby silica gel column chromatography eluting with 5% MeOH in DCM toafford the title compound as a colorless oil (270 mg, 57%). ¹H NMR (400MHz, DMSO-d₆): δ ppm −0.01 (s, 9H), 0.82 (t, 2H), 2.01 (s, 3H), 2.09 (s,3H), 3.43 (t, 2H), 5.18 (s, 2H), 7.52 (s, 1H).

Biological Evaluation

JAK Caliper Enzyme Assay at 1 mM ATP

Test article was solubilized in dimethyl sulfoxide (DMSO) to a stockconcentration of 30 mM. An 11-point half log dilution series was createdin DMSO with a top concentration of 600 μM. The test compound plate alsocontained positive control wells containing a known inhibitor to define100% inhibition and negative control wells containing DMSO to define noinhibition. The compound plates were diluted 1 to 60 resulting in a topfinal assay compound concentration of 10 μM and a 2% DMSO concentration.

Test article and assay controls were added to a 384-well plate. Reactionmixtures contained 20 mM HEPES, pH 7.4, 10 mM magnesium chloride, 0.01%bovine serum albumin (BSA), 0.0005% Tween 20, 1 mM ATP and 1 μM peptidesubstrate. The JAK1 and TYK2 assays contained 1 μM of the IRStidepeptide (5FAM-KKSRGDYMTMQID) and the JAK2 and JAK3 assays contained 1 μMof the JAKtide peptide (FITC-KGGEEEEYFELVKK). The assays were initiatedby the addition of 20 nM JAK1, 1 nM JAK2, 1 nM JAK3 or 1 nM TYK2 enzymeand were incubated at room temperature for three hours for JAK1, 60minutes for JAK2, 75 minutes for JAK3 or 135 minutes for TYK2. Enzymeconcentrations and incubation times were optimized for each new enzymepreps and were modified slightly over time to ensure 20%-30%phosphorylation. The assays were stopped with a final concentration of10 mM EDTA, 0.1% Coating Reagent and 100 mM HEPES, pH=7.4. The assayplates were placed on a Caliper Life Science Lab Chip 3000 (LC3000)instrument, and each well was sampled using appropriate separationconditions to measure the unphosphorylated and phosphorylated peptide.

A549 Cell Assay: Inhibition of pSTAT3

An assay measuring the efficacy of JAK inhibitors on the functionalresponse of recombinant human interferon γ (rhIFNγ) stimulated STAT-3phosphorylation in the A549 human epithelial cell line.

Method

A549 cells (ATCC #CCL-185), were plated at 30,000 cells/well in 96 wellflat bottomed tissue culture plates (BD#353072) in 200 μL of growthmedium (DMEM, Pfizer media prep, with 10% Fetal Bovine Serum, Sigma#F4135, 2 mM L-Glutamine, Pfizer media prep, 100 U/mL penicillin, Pfizermedia prep, and 200 μg/ml streptomycin, Pfizer media prep), and culturedat 37° C., 5% CO₂ incubator for 18 hours. Growth medium was removed byvacuum aspiration (V&P Scientific #vp187 bp-60), and 90 μL of pre-warmedassay medium (DMEM with 0.2% BSA, Miltenyi #130-091-376) was added toeach well and incubated for 15 minutes at 37° C. 10 μL of vehiclecontrol or test compound (final concentration range of 0.3 nM to 10 μMwith 0.1% DMSO) was added to the cells. Plates were incubated at 37° C.for 1 hour. After compound incubation, 10 μL of 220 ng/mL recombinanthuman IFNγ (R&D Systems #285-IF, final rhIFNγ concentration of 20 ng/mL)was added to the cells and plates were incubated for 30 minutes at 37°C. Wells containing A549 cells, medium with 0.1% DMSO and no rhIFNγ wereused as background controls. After rhIFNγ stimulation, media wasaspirated from each well and 35 μL/well of iced-cold MSD lysis buffercontaining protease and phosphatase inhibitors from Phospho-STAT3 Tyr705assay kit (Meso-Scale Discovery #K150DID) was added to each well. Plateswere incubated at 4° C. with shaking for 30 minutes. Cell lysates wereassayed following the MSD Phospho-STAT3 Tyr705 assay kit protocol todetect pSTAT3.

Data were collected and transformed into percent inhibition andcalculated using the following formula:

${\% \mspace{14mu} {Inhibition}} = {\left( {1 - \left( \frac{{{Compound}\mspace{14mu} {pSTAT}\; 3} - {{Basal}\mspace{14mu} {pSTAT}\; 3}}{{{No}\mspace{14mu} {Compound}\mspace{14mu} {Control}\mspace{14mu} {pSTAT}\; 3} - {{Basal}\mspace{14mu} {pSTAT}\; 3}} \right)} \right)*100}$

Data were graphically displayed as percent inhibition using GraphPadPrism 4.0, and IC₅₀ curves were fitted using a point to point analysis.

Human T Cell Assay: Inhibition of pSTAT5

An assay measuring the efficacy of JAK inhibitors on the functionalresponse of recombinant human interleukin-2 (rhIL-2) stimulated STAT5phosphorylation in isolated human T cells.

Method:

Human whole blood from individual donors was collected from thephlebotomy unit on-site. Peripheral venous blood (30-60 mL) from healthyvolunteers of either sex was used as the source of T cells. T cellisolation from venous whole blood is routinely performed in a class IImicrobiological safety cabinet. Each sample was collected into between 3and 6 10 mL Sodium Heparin Vacutainer tubes (BD #367874). The blood waspoured into sterile 50 mL conicals (Corning #430828) and incubated withthe T cell Rosette Sep Cocktail (Stemcell Technologies #15061) at 50μL/mL antibody/blood ratio for 20 min. with shaking at room temperature.The blood/antibody mixture was then diluted 1:2 with PBS (Pfizer mediaprep)/2% FBS (Sigma #F4135) and 30 mL of the mixture was layered onto 15mL Ficoll-Hypaque (GE Healthcare #17-1440-03) in 50 mL conical tubes.The tubes were then centrifuged at 1200×g for 20 min. at roomtemperature with no brake. Following centrifugation the T cells formed abuffy coat between the Ficoll-Hypaque and plasma layers. The plasmaabove the buffy coats was removed to within 5 mm of the buffy coat usinga sterile Pasteur pipette. The buffy coats were then collected intofresh sterile 50 mL conical tubes containing 25 mL PBS/2% FBS (2 buffycoats per 50 mL conical). PBS/2% FBS was added to the buffy coat cellssuch that the final volume in the tube was 50 mL. The tubes were thencentrifuged at 200×g for 15 min. at room temperature. The supematant wasdiscarded and the pellet re-suspended in 10-20 mL of DMEM (Pfizer mediaprep) Assay media/0.2% BSA (Miltenyi #130-091-376). A differential cellcount was performed using a haemacytometer and cells were diluted to1.1×10⁶ T cells/ml in DMEM/0.2% BSA media. Compounds (10 mM-0.3 μM) werediluted with Hanks Balanced Salt Solution (HBSS) (Sigma #H6648) at 1:100dilution. Immediately following cell isolation and compound dilution, 90μl/well of T cells (˜1×10⁶/ml) in assay medium (DMEM+0.2% BSA) was addedto the VWR Deep well V bottom plate (#3906-520-300). 10 μl/well ofcompound (final concentration range of 10 μM-0.3 nM with 0.1% DMSO) or0.1% DMSO in HBSS as controls was added to the appropriate wells. Plateswere incubated for 1 hour at 37° C., 5% CO₂ incubator. 10 μl of 3.3μg/mL rhIL-2 (R&D Systems #202-IL) was added to the cells (300 ng/mlfinal assay concentration). Wells containing T cells, medium with 0.1%DMSO and no rhIL-2 were used as background controls. Plates wereincubated for 15 min at 37° C. After rhIL-2 stimulation, 800 μL of coldPBS/0.1% BSA was added and the plates were centrifuged at 1400 rpm for 5min at 4° C. Supematant was aspirated and 100 μL of ice-cold MSD lysisbuffer containing protease and phosphatase inhibitors fromPhospho-STAT5a/b Tyr694 assay kit (Meso-Scale Discovery #K150IGD) wasadded to the cell pellet. Plates were shaken for 30 min. at 4° C. andthen frozen overnight. The following day, cell lysates were assayedusing the MSD ELISA kit protocol for detection of pSTAT5.

Data were collected and transformed into percent inhibition andcalculated using the following formula:

${\% \mspace{14mu} {Inhibition}} = {\left( {1 - \left( \frac{{{Compound}\mspace{14mu} {pSTAT}\; 5} - {{Basal}\mspace{14mu} {pSTAT}\; 5}}{{{No}\mspace{14mu} {Compound}\mspace{14mu} {Control}\mspace{14mu} {pSTAT}\; 5} - {{Basal}\mspace{14mu} {pSTAT}\; 5}} \right)} \right)*100}$

Data were graphically displayed as percent inhibition using GraphPadPrism 4.0, and IC₅₀ curves were fitted using a point to point analysis.

TABLE 1 Data for JAK Caliper ™ Kinase assays at 1 mM ATP and Cell Basedassays Cell Based Assays Human T A549 cell cell Caliper ™ Assays atassay: assay: 1 mM ATP Inhibition Inhibition JAK1 JAK2 JAK3 TYK2 of ofIC₅₀ IC₅₀ IC₅₀ IC₅₀ pSTAT3 pSTAT5 Ex. Structure (nM) (nM) (nM) (nM) IC₅₀(nM ) IC₅₀ (nM) 125

0.2 1.0 4.4 5.6 126

8.1 23.5 35.1 668.3 127

6.0 14.9 53.3 624.9 131

<0.5 2.1 10.2 4.7 7.4 24.3 124

87.6 182.6 156.7 4234.5 123

3.3 4.5 9.5 82.1 128

3.6 12.6 30.5 514.3 132

19.0 31.4 18.4 1293.1 256.5 206.4 111

13.8 52.4 193.6 1540.2 112

12.1 82.9 67.5 5170.8 113

10.7 26.3 42.4 723.1 114

10.1 25.9 56.2 289.2 115

4.3 10.1 16.8 229.0 116

3.8 10.1 23.3 162.7 117

7.2 5.0 41.6 425.0 118

67.4 118.9 339.6 2730.0 119

39.4 46.5 111.0 561.1 120

10.8 127.8 89.2 3320.1 121

9.7 16.9 40.8 302.1 122

14.9 25.1 78.1 478.4 137

<0.1 0.3 3.3 45.4 138

0.6 2.6 14.2 4.8 5.4 139

8.5 16.7 27.5 1992.6 133

1.2 5.9 30.5 249.3 10.1 34.7 135

0.7 3.4 17.3 8.4 3.3 145

1.0 4.5 16.2 15.8 15.7 157.3 141

19.5 43.2 61.6 7069.4 140

18.1 53.5 131.1 1410.3 147

1.1 4.7 18.5 49.4 142

3.4 7.9 27.9 885.1 143

40.4 43.6 121.9 4663.2 144

55.3 70.7 185.9 8734.3 146

0.9 5.1 19.1 49.9 7.6 62.3 148

1.8 6.3 22.8 145.6 14.9 149

2.7 14.5 22.7 763.5 150

21.6 48.9 77.8 4156.1 19

0.9 5.9 30.9 4.8 11.9 20.2 134

<0.5 1.7 7.6 20.3 258.6 136

0.8 4.3 22.4 8.7 13.3 155

1.2 5.0 15.5 61.0 30.1 129

11.6 43.7 180.1 56.6 62.4 130

43.8 154.9 1358.2 194.1 728.6 5

2.1 7.5 31.9 7.0 1.7 20

3.6 16.6 95.3 20.9 18.8 31.9 3

1.9 9.6 47.5 6.8 16.2 6

3.1 15.8 84.9 15.3 23.4 8

1.7 7.5 33.8 5.7 6.4 7

1.7 9.2 49.0 6.5 5.7 21

2.7 13.2 67.9 11.4 35.6 9

1.7 10.8 60.0 7.2 14.9 2

3.4 17.0 84.5 12.1 46.8 10

4.7 19.0 93.1 17.9 26 11

8.7 36.9 206.6 229.4 72.4 14

4.2 20.5 99.7 43.2 20.7 1

8.0 38.1 176.8 36.5 67.4 15

13.6 55.0 342.4 618.3 92.4 93

2.0 8.4 27.4 13.9 31.9 40.4 16

6.3 23.0 130.8 66.0 65.1 18

4.0 17.4 73.0 31.0 97 17

18.5 52.9 255.7 142.4 173.9 13

5.3 26.6 118.0 35.7 96.7 12

6.4 31.5 120.6 24.8 44.9 4

1.7 6.2 26.6 15.3 29.7 56

6.6 26.1 134.8 19.9 276.9 53.4 31

1.3 7.0 33.0 4.6 74 48.2 22

17.5 81.3 359.0 59.1 52.8 23

5.8 25.7 110.7 83.2 51.4 165

3.5 16.9 78.0 14.6 566.7 91.3 38

4.0 25.0 121.8 17.8 30.8 39

32.3 48.2 278.5 320.3 60.9 162

4.1 23.6 90.6 15.4 20 157

3.4 15.0 76.5 11.7 26.2 94

5.4 27.7 71.2 503.4 125.5 158

5.3 27.8 114.0 33.3 31.3 159

4.3 18.5 83.3 16.1 18.7 163

32.9 150.2 491.0 355.9 98.6 76

29.6 112.9 475.0 315.5 324.8 120.7 171

27.5 128.9 428.9 150.2 1575.2 1090.4 92

2.1 13.5 45.7 14.5 398.2 343.4 77

3.3 15.1 63.6 27.1 32.9 59.9 166

20.9 97.4 322.5 126.5 697.3 590.8 164

4.5 22.2 91.0 24.2 3022.5 3897.0 98

4.9 18.3 39.6 600.3 723.6 324.5 170

3.2 12.7 38.0 373.4 1356.3 767.2 169

10.5 22.9 59.8 305.7 >10000 109

6.4 31.2 107.3 674.2 73

5.4 18.8 80.9 33.9 35.6 167

4.1 16.0 47.4 310.0 >10000 168

15.7 59.5 121.7 1156.7 1327.4 161

16.8 54.3 157.6 2260.9 >10000 102

5.6 35.3 110.6 68.6 3357.9 105

3.2 14.4 51.2 14.0 7023.2 110

5.4 26.9 120.4 35.0 >10000 74

14.7 68.7 208.9 215.7 50

1.7 10.7 47.4 10.5 320.8 106

41.2 283.2 210.6 6111.8 2517.2 51

3.5 20.8 66.9 226.4 182.5 40

4.6 23.1 130.3 18.1 50 173

9.3 50.3 133.9 180.1 220.3 26

19.9 91.1 293.3 217.5 124.5 107

50.0 196.3 589.0 172.5 898.7 95

6.7 27.0 82.4 89.3 59.9 108

50.5 123.5 197.7 5692.8 1504.2 100

8.7 32.3 61.9 1149.1 6880.8 152

41.6 228.0 156.7 3673.3 133.2 151

33.9 168.9 124.7 2976.2 133.4 154

77.6 301.6 228.0 5136.3 153

74.0 241.2 207.0 7458.4 24

2.9 16.5 69.6 29.9 226.4 27

2.9 14.7 53.5 48.8 873.6 101

10.5 41.3 51.1 1956.2 >10000 29

1.5 8.5 33.2 19.0 86.9 30

1.0 5.8 23.3 29.0 163.5 99

6.8 26.9 62.4 425.6 2465.9 33

5.7 25.0 75.2 281.9 490.1 103

5.0 31.0 92.6 349.0 235 32

60.4 276.8 839.2 373.4 627.5 90

2.7 18.1 77.1 23.2 30.4 34

5.1 27.8 98.4 24.6 300.6 41

27.4 142.0 383.2 1188.3 1185.0 48

67.6 188.4 148.5 6329.8 >10000 75

61.1 320.9 755.3 1935.5 1345.1 35

39.9 249.0 816.9 256.4 437.4 96

30.5 122.6 247.5 1734.4 2871.2 97

55.1 204.6 414.6 2193.5 2073.3 36

75.0 401.0 1226.6 364.4 433.1 68

14.2 72.7 252.8 72.3 43.9 42

25.3 158.4 534.0 233.3 645 43

55.1 302.0 1068.7 438.7 763.5 45

4.0 18.9 68.7 148.5 46.5 57

21.1 93.4 408.7 148.7 60.4 46

32.9 101.0 179.0 1032.8 103.4 44

25.8 85.2 292.6 999.0 59.7 58

10.3 54.4 236.5 67.5 173.7 59

5.3 23.5 112.4 22.6 290.5 53

9.7 33.1 102.3 242.9 21.3 88

6.6 41.1 139.7 127.3 31.5 52

2.9 15.0 46.3 109.2 74.3 62

2.9 14.4 39.5 278.0 71.8 63

5.0 22.5 82.1 107.0 14.6 104

10.4 66.1 112.7 1377.4 292.2 54

6.1 32.9 122.7 25.9 134.6 64

3.3 11.1 36.9 153.1 212.7 55

2.1 13.7 54.0 45.9 155.6 37

5.0 19.7 52.0 169.0 47.4 60

6.6 29.2 115.2 56.5 34.4 47

10.6 28.4 54.3 320.2 281.9 65

23.3 83.8 283.3 125.8 160.9 69

16.2 63.7 256.8 66.8 91.6 61

7.3 30.2 110.5 52.3 71.2 70

12.0 52.4 207.9 79.4 46.2 89

14.6 57.1 211.6 916.9 46.3 67

16.3 48.2 72.8 2028.3 104.1 66

3.5 14.8 60.0 81.3 221.2 86

38.4 110.3 81.7 4819.5 425 49

78.0 181.1 248.0 3603.3 385.3 87

30.6 87.8 133.4 2486.5 213.2 84

27.6 142.3 537.3 880.1 32.9 83

12.1 63.3 201.2 139.1 30 91

28.7 127.7 462.5 865.2 26.3 71

44.1 156.5 359.0 2753.5 110.1 72

44.8 134.9 197.9 3445.7 94.1 156

25.5 120.4 176.8 9995.0 72.4 85

7.8 47.2 155.9 81.4 12.9 78

5.9 39.4 89.9 930.1 27.2 79

10.7 59.1 175.0 698.4 30.7 80

2.9 16.2 49.2 167.4 197 82

13.7 83.9 313.1 121.2 20.9 81

4.7 27.1 102.8 297.5

1-13. (canceled)
 14. A method of treating a disease or conditionselected from allergic rhinitis, nasal congestion, rhinorrhea, perennialrhinitis, nasal inflammation, asthma of all types, chronic obstructivepulmonary disease, chronic or acute bronchoconstriction, chronicbronchitis, small airways obstruction, emphysema, chronic eosinophilicpneumonia, adult respiratory distress syndrome, exacerbation of airwayshyper-reactivity consequent to other drug therapy, pulmonary vasculardisease, pulmonary arterial hypertension, acute lung injury,bronchiectasis, sinusitis, allergic conjunctivitis, idiopathic pulmonaryfibrosis or atopic dermatitis, comprising administering to the subject atherapeutically effective amount of a compound [of claim 1] having thestructure:

or a pharmaceutically acceptable salt thereof, or a pharmaceuticallyacceptable solvate of said compound or pharmaceutically acceptable salt,wherein: A and A′ are independently C or N, where C may be unsubstitutedor substituted by halo or C₁-C₆ alkyl; R and R⁰ are independentlyselected from the group consisting of H, C₁-C₆ alkyl, hydroxy(C₁-C₆alkyl), phenyl(C₁-C₆ alkyl), and —(CH₂)_(n)—W, where W is C₃-C₈cycloalkyl, phenyl, naphthyl, 5- or 6-membered heteroaryl orheterocyclic containing 1-3 N, S and/or O atoms, —SO₂—R′, —NHSO₂—R′,—NR″SO₂—R′ and SR′, where R′ and R″ are independently C₁-C₆ alkyl orC₃-C₈ cycloalkyl, amino, C₁-C₆ alkylamino, di(C₁-C₆ alkyl)amino, phenyl,heteroaryl, or heterocyclic; wherein each of said alkyl, cycloalkyl,heterocyclic, phenyl, naphthyl or heteroaryl may be unsubstituted orsubstituted by phenyl, heteroaryl, heterocyclic, halo, cyano, hydroxy,C₁-C₆ alkyl, C₁-C₆ alkoxy, aryloxy, —SO₂—R′, —CONR′R″, NR′COR″,—NR′CONR′R″, —NR′CO₂R″, —(CH₂)_(n)—SO₂—R′, —NHSO₂—R′, —NR″SO₂—R′ or SR′where R′ and R″ are independently C₁-C₆ alkyl, C₃-C₈ cycloalkyl, phenyl,amino, hydroxyalkylamino, heterocyclic, or —(CH₂)_(n)—W, where W ishydroxy, C₃-C₈ cycloalkyl, phenyl, naphthyl, heterocyclic, or 5- or6-membered heteroaryl containing 1-3 N, S and/or O atoms; or, R and R⁰and the N atom to which they are bonded together form a monocyclic orbicyclic heterocyclic ring which may be unsubstituted or substituted by(a) halo, hydroxy, heteroaryl, C₁-C₆ alkyl, C₁-C₆ alkoxy, (C₁-C₆alkoxy)C₁-C₆ alkoxy, aryl(C₁-C₆ alkoxy), aryloxy, amino, aminoacyl,C₁-C₆ alkylaminoacyl, arylalkylaminoacyl, di(C₁-C₆ alkyl)aminoacyl,—SO₂—R′, —SO₂—NR″—(CH₂)_(n)—W, —NHSO₂—R′, —NR″SO₂—R′ or SR′ where R′ andR″ is independently amino, C₁-C₆ alkylamino, di(C₁-C₆ alkyl)amino, C₁-C₆alkyl or C₃-C₈ cycloalkyl, or (b) —(CH₂)_(n)—W, where W is C₃-C₈cycloalkyl, phenyl, naphthyl, heterocyclic, 5- or 6-membered heteroarylcontaining 1-3 N atoms, —SO₂—R′, —NHSO₂—R′, —NR″SO₂—R′ or SR′, where R′and R″ is independently alkyl or cycloalkyl; wherein each of saidphenyl, aryl, or heteroaryl may be unsubstituted or substituted by halo,C₁-C₆ alkyl, C₁-C₆ alkoxy, cyano, or hydroxy; R¹ is H, halo or cyano; R²and R^(2′) are independently H, C₁-C₆ alkyl, cyano, C₁-C₆ alkoxy, C₁-C₆alkylthio, or C₃-C₈ cycloalkyl where alkyl, alkoxy, or cycloalkyl isoptionally substituted by one or more fluorine atoms; X is a bond, —CO—,—CONH—, —SO₂—, —SONH—, or —(CH₂)_(m)—; R³ is H, C₁-C₄ alkyl, phenyl,naphthyl, 6-membered heteroaryl or heterocyclic containing 1-3 N atoms,a 5-membered heteroaryl or heterocyclic containing either (a) 1-4 Natoms or (b) 1 O or S atom and 0-3 N atoms, a 10-membered bicyclicheteroaryl or heterocyclic containing 1-4 N atoms, a 9-membered bicyclicheteroaryl or heterocyclic containing either (a) 1-4 N atoms or (b) 1 Oor S atom and 0-3 N atoms, or an 8-membered bicyclic heteroaryl orheterocyclic containing (a) 1-4 N atoms or (b) 1 O or S atom and 1-3 Natoms or (c) 2 O or S atoms and 0-2 N atoms; wherein each of saidphenyl, naphthyl, heteroaryl or heterocyclic is optionally substitutedby alkyl, 1 substituent —Y—R⁴ and/or 1-4 substituents each independentlyselected from R⁵; with the proviso that when X is —CO— or —SO₂—, R³ isnot H; Y is a bond, —(CH₂)_(m)— or —O—; R⁴ is (a) H, C₁-C₆ alkyl, C₃-C₈cycloalkyl, halo, oxo, —OR⁶, —NR⁷R⁸, —SR⁶, —SOR⁹, —SO₂R⁹, —COR⁶, —OCOR⁶,—COOR⁶, —NR⁶COR⁶, —CONR⁷R⁸, —NR⁶SO₂R⁹, —SO₂NR⁷R⁸, —NR⁶CONR⁷R⁸, —NR⁶COOR⁹and —NR⁶SO₂NR⁷R⁸; (b) phenyl or naphthyl, said phenyl and naphthyl beingoptionally substituted with 1-5 substituents selected from C₁-C₆ alkyl,C₃-C₈ cycloalkyl, halo, —CN, —OR⁶, —NR⁷R⁸, —SR⁶, —SOR⁹, —SO₂R⁹, —COR⁶,—OCOR⁶, —COOR⁶, —NR⁶COR⁶, —CONR⁷R⁸, —NR⁶SO₂R⁹, —SO₂NR⁷R⁸, —NR⁶CONR⁷R⁸,—NR⁶COOR⁹ and —NR⁶SO₂NR⁷R⁸; or (c) a 3 to 8-membered saturated orpartially unsaturated monocyclic heteroaryl, containing 1 or 2heteroatoms selected from O and N, said heteroaryl being optionallysubstituted by 1-5 substituents selected from C₁-C₆ alkyl, C₃-C₈cycloalkyl, halo, oxo, —OR⁶, —NR⁷R⁸, —SR⁶, —SOR⁹, —SO₂R⁹, —COR⁶, —OCOR⁶,—COOR⁶, —NR⁶COR⁶, —CONR⁷R⁸, —NR⁶SO₂R⁹, —SO₂NR⁷R⁸, —NR⁶CONR⁷R⁸, —NR⁶COOR⁹and —NR⁶SO₂NR⁷R⁸; R⁵ is C₁-C₆ alkyl, C₃-C₈ cycloalkyl, halo, —CN, —OR⁶,—NR⁷R⁸, —SR⁶, —SOR⁹, —SO₂R⁹, —COR⁶, —OCOR⁶, —COOR⁶, —NR⁶COR⁶, —CONR⁷R⁸,—NR⁶SO₂R⁹, —SO₂NR⁷R⁸, —NR⁶CONR⁷R⁸, —NR⁶COOR⁹ or —NR⁶SO₂NR⁷R⁸; R⁶ is H,C₁-C₆ alkyl or C₃-C₈ cycloalkyl, said C₁-C₆ alkyl is optionallysubstituted by —NR⁷R⁸ or a 3 to 8-membered saturated or partiallyunsaturated monocyclic heteroaryl, containing 1 or 2 heteroatomsselected from O and N, said heteroaryl being optionally substituted by1-5 substituents selected from C₁-C₆ alkyl, C₃-C₈ cycloalkyl, halo,hydroxy and cyano; R⁷ and R⁸ are each independently H, C₁-C₆ alkyl orC₃-C₈ cycloalkyl or are taken together with the nitrogen atom to whichthey are attached to form a 4-, 5- or 6-membered saturated heterocyclicring containing 1-2 nitrogen atoms or 1 nitrogen and 1 oxygen atom, saidC₁-C₆ alkyl is optionally substituted by C₃-C₈ cycloalkyl, halo, cyano,hydroxy, amino, (C₁-C₆ alkyl)amino or di(C₁-C₆ alkyl)amino and saidheterocyclic ring being optionally substituted by one or more C₁-C₆alkyl or C₃-C₈ cycloalkyl groups; R⁹ is C₁-C₆ alkyl or C₃-C₈ cycloalkyl;and, m and n are independently 0, 1, 2 or 3, or a pharmaceuticallyacceptable salt thereof, or a pharmaceutically acceptable solvate ofsaid compound or salt.
 15. A method of treating a disease or conditionselected from inflammation, neuroinflammation, arthritis, rheumatoidarthritis, spondyloarthropathies, systemic lupus erythematous arthritis,osteoarthritis, gouty arthritis, pain, fever, pulmonary sarcoisosis,silicosis, cardiovascular disease, atherosclerosis, myocardialinfarction, thrombosis, congestive heart failure and cardiac reperfusioninjury, cardiomyopathy, stroke, ischaemia, reperfusion injury, brainedema, brain trauma, neurodegeneration, liver disease, inflammatorybowel disease, Crohn's disease, ulcerative colitis, nephritis,retinitis, retinopathy, macular degeneration, glaucoma, diabetes (type 1and type 2), diabetic neurorpathy, viral and bacterial infection,myalgia, endotoxic shock, toxic shock syndrome, autoimmune disease,osteoporosis, multiple sclerosis, endometriosis, menstrual cramps,vaginitis, candidiasis, cancer, fibrosis, obesity, muscular dystrophy,polymyositis, Alzheimer's disease, skin flushing, eczema, psoriasis,atopic dermatitis and sunburn, comprising administering to the subject atherapeutically effective amount of a compound [of claim 1] having thestructure:

or a pharmaceutically acceptable salt thereof, or a pharmaceuticallyacceptable solvate of said compound or pharmaceutically acceptable salt,wherein: A and A′ are independently C or N, where C may be unsubstitutedor substituted by halo or C₁-C₆ alkyl; R and R⁰ are independentlyselected from the group consisting of H, C₁-C₆ alkyl, hydroxy(C₁-C₆alkyl), phenyl(C₁-C₆ alkyl), and —(CH₂)_(n)—W, where W is C₃-C₈cycloalkyl, phenyl, naphthyl, 5- or 6-membered heteroaryl orheterocyclic containing 1-3 N, S and/or O atoms, —SO₂—R′, —NHSO₂—R′,—NR″SO₂—R′ and SR′, where R′ and R″ are independently C₁-C₆ alkyl orC₃-C₈ cycloalkyl, amino, C₁-C₆ alkylamino, di(C₁-C₆ alkyl)amino, phenyl,heteroaryl, or heterocyclic; wherein each of said alkyl, cycloalkyl,heterocyclic, phenyl, naphthyl or heteroaryl may be unsubstituted orsubstituted by phenyl, heteroaryl, heterocyclic, halo, cyano, hydroxy,C₁-C₆ alkyl, C₁-C₆ alkoxy, aryloxy, —SO₂—R′, —CONR′R″, NR′COR″,—NR′CONR′R″, —NR′CO₂R″, —(CH₂)_(n)—SO₂—R′, —NHSO₂—R′, —NR″SO₂—R′ or SR′where R′ and R″ are independently C₁-C₆ alkyl, C₃-C₈ cycloalkyl, phenyl,amino, hydroxyalkylamino, heterocyclic, or —(CH₂)_(n)—W, where W ishydroxy, C₃-C₈ cycloalkyl, phenyl, naphthyl, heterocyclic, or 5- or6-membered heteroaryl containing 1-3 N, S and/or O atoms; or, R and R⁰and the N atom to which they are bonded together form a monocyclic orbicyclic heterocyclic ring which may be unsubstituted or substituted by(a) halo, hydroxy, heteroaryl, C₁-C₆ alkyl, C₁-C₆ alkoxy, (C₁-C₆alkoxy)C₁-C₆ alkoxy, aryl(C₁-C₆ alkoxy), aryloxy, amino, aminoacyl,C₁-C₆ alkylaminoacyl, arylalkylaminoacyl, di(C₁-C₆ alkyl)aminoacyl,—SO₂—R′, —SO₂—NR″—(CH₂)_(n)—W, —NHSO₂—R′, —NR″SO₂—R′ or SR′ where R′ andR″ is independently amino, C₁-C₆ alkylamino, di(C₁-C₆ alkyl)amino, C₁-C₆alkyl or C₃-C₈ cycloalkyl, or (b) —(CH₂)_(n)—W, where W is C₃-C₈cycloalkyl, phenyl, naphthyl, heterocyclic, 5- or 6-membered heteroarylcontaining 1-3 N atoms, —SO₂—R′, —NHSO₂—R′, —NR″SO₂—R′ or SR′, where R′and R″ is independently alkyl or cycloalkyl; wherein each of saidphenyl, aryl, or heteroaryl may be unsubstituted or substituted by halo,C₁-C₆ alkyl, C₁-C₆ alkoxy, cyano, or hydroxy; R¹ is H, halo or cyano; R²and R^(2′) are independently H, C₁-C₆ alkyl, cyano, C₁-C₆ alkoxy, C₁-C₆alkylthio, or C₃-C₈ cycloalkyl where alkyl, alkoxy, or cycloalkyl isoptionally substituted by one or more fluorine atoms; X is a bond, —CO—,—CONH—, —SO₂—, —SONH—, or —(CH₂)_(m)—; R³ is H, C₁-C₄ alkyl, phenyl,naphthyl, 6-membered heteroaryl or heterocyclic containing 1-3 N atoms,a 5-membered heteroaryl or heterocyclic containing either (a) 1-4 Natoms or (b) 1 O or S atom and 0-3 N atoms, a 10-membered bicyclicheteroaryl or heterocyclic containing 1-4 N atoms, a 9-membered bicyclicheteroaryl or heterocyclic containing either (a) 1-4 N atoms or (b) 1 Oor S atom and 0-3 N atoms, or an 8-membered bicyclic heteroaryl orheterocyclic containing (a) 1-4 N atoms or (b) 1 O or S atom and 1-3 Natoms or (c) 2 O or S atoms and 0-2 N atoms; wherein each of saidphenyl, naphthyl, heteroaryl or heterocyclic is optionally substitutedby alkyl, 1 substituent —Y—R⁴ and/or 1-4 substituents each independentlyselected from R⁵; with the proviso that when X is —CO— or —SO₂—, R³ isnot H; Y is a bond, —(CH₂)_(m)— or —O—; R⁴ is (a) H, C₁-C₆ alkyl, C₃-C₈cycloalkyl, halo, oxo, —OR⁶, —NR⁷R⁸, —SR⁶, —SOR⁹, —SO₂R⁹, —COR⁶, —OCOR⁶,—COOR⁶, —NR⁶COR⁶, —CONR⁷R⁸, —NR⁶SO₂R⁹, —SO₂NR⁷R⁸, —NR⁶CONR⁷R⁸, —NR⁶COOR⁹and —NR⁶SO₂NR⁷R⁸; (b) phenyl or naphthyl, said phenyl and naphthyl beingoptionally substituted with 1-5 substituents selected from C₁-C₆ alkyl,C₃-C₈ cycloalkyl, halo, —CN, —OR⁶, —NR⁷R⁸, —SR⁶, —SOR⁹, —SO₂R⁹, —COR⁶,—OCOR⁶, —COOR⁶, —NR⁶COR⁶, —CONR⁷R⁸, —NR⁶SO₂R⁹, —SO₂NR⁷R⁸, —NR⁶CONR⁷R⁸,—NR⁶COOR⁹ and —NR⁶SO₂NR⁷R⁸; or (c) a 3 to 8-membered saturated orpartially unsaturated monocyclic heteroaryl, containing 1 or 2heteroatoms selected from O and N, said heteroaryl being optionallysubstituted by 1-5 substituents selected from C₁-C₆ alkyl, C₃-C₈cycloalkyl, halo, oxo, —OR⁶, —NR⁷R⁸, —SR⁶, —SOR⁹, —SO₂R⁹, —COR⁶, —OCOR⁶,—COOR⁶, —NR⁶COR⁶, —CONR⁷R⁸, —NR⁶SO₂R⁹, —SO₂NR⁷R⁸, —NR⁶CONR⁷R⁸, —NR⁶COOR⁹and —NR⁶SO₂NR⁷R⁸; R⁵ is C₁-C₆ alkyl, C₃-C₈ cycloalkyl, halo, —CN, —OR⁶,—NR⁷R⁸, —SR⁶, —SOR⁹, —SO₂R⁹, —COR⁶, —OCOR⁶, —COOR⁶, —NR⁶COR⁶, —CONR⁷R⁸,—NR⁶SO₂R⁹, —SO₂NR⁷R⁸, —NR⁶CONR⁷R⁸, —NR⁶COOR⁹ or —NR⁶SO₂NR⁷R⁸; R⁶ is H,C₁-C₆ alkyl or C₃-C₈ cycloalkyl, said C₁-C₆ alkyl is optionallysubstituted by —NR⁷R⁸ or a 3 to 8-membered saturated or partiallyunsaturated monocyclic heteroaryl, containing 1 or 2 heteroatomsselected from O and N, said heteroaryl being optionally substituted by1-5 substituents selected from C₁-C₆ alkyl, C₃-C₈ cycloalkyl, halo,hydroxy and cyano; R⁷ and R⁸ are each independently H, C₁-C₆ alkyl orC₃-C₈ cycloalkyl or are taken together with the nitrogen atom to whichthey are attached to form a 4-, 5- or 6-membered saturated heterocyclicring containing 1-2 nitrogen atoms or 1 nitrogen and 1 oxygen atom, saidC₁-C₆ alkyl is optionally substituted by C₃-C₈ cycloalkyl, halo, cyano,hydroxy, amino, (C₁-C₆ alkyl)amino or di(C₁-C₆ alkyl)amino and saidheterocyclic ring being optionally substituted by one or more C₁-C₆alkyl or C₃-C₈ cycloalkyl groups; R⁹ is C₁-C₆ alkyl or C₃-C₈ cycloalkyl;and, m and n are independently 0, 1, 2 or 3, or a pharmaceuticallyacceptable salt thereof, or a pharmaceutically acceptable solvate ofsaid compound or salt.
 16. The method of claim 14, wherein the compoundhas the structure:

or a pharmaceutically acceptable salt thereof, or a pharmaceuticallyacceptable solvate of said compound or pharmaceutically acceptable salt,wherein: A, A″ and A′″ are independently C or N, where C may beunsubstituted or substituted by halo or C₁-C₆ alkyl; R¹ is H, cyano orhalo; R² and R^(2′) are independently H, C₁-C₆ alkyl, cyano, C₁-C₆alkoxy, C₁-C₆ alkylthio, or C₃-C₈ cycloalkyl where alkyl, alkoxy, orcycloalkyl is optionally substituted by one or more fluorine atoms; R³is H, C₁-C₄ alkyl, phenyl, naphthyl, 6-membered heteroaryl orheterocyclic containing 1-3 N atoms, a 5-membered heteroaryl orheterocyclic containing either (a) 1-4 N atoms or (b) 1 O or S atom and0-3 N atoms, a 10-membered bicyclic heteroaryl or heterocycliccontaining 1-4 N atoms, a 9-membered bicyclic heteroaryl or heterocycliccontaining either (a) 1-4 N atoms or (b) 1 O or S atom and 0-3 N atoms,or an 8-membered bicyclic heteroaryl or heterocyclic containing (a) 1-4N atoms or (b) 1 O or S atom and 1-3 N atoms or (c) 2 O or S atoms and0-2 N atoms; wherein each of said phenyl, naphthyl, heteroaryl orheterocyclic is optionally substituted by alkyl, 1 substituent —Y—R⁴and/or 1-4 substituents each independently selected from R⁵; Y is abond, —(CH₂)_(m)— or —O—; R⁴ is (a) H, C₁-C₆ alkyl, C₃-C₈ cycloalkyl,halo, oxo, —OR⁶, —NR⁷R⁸, —SR⁶, —SOR⁹, —SO₂R⁹, —COR⁶, —OCOR⁶, —COOR⁶,—NR⁶COR⁶, —CONR⁷R⁸, —NR⁶SO₂R⁹, —SO₂NR⁷R⁸, —NR⁶CONR⁷R⁸, —NR⁶COOR⁹ and—NR⁶SO₂NR⁷R⁸; (b) phenyl or naphthyl, said phenyl and naphthyl beingoptionally substituted with 1-5 substituents selected from C₁-C₆ alkyl,C₃-C₈ cycloalkyl, halo, —CN, —OR⁶, —NR⁷R⁸, —SR⁶, —SOR⁹, —SO₂R⁹, —COR⁶,—OCOR⁶, —COOR⁶, —NR⁶COR⁶, —CONR⁷R⁸, —NR⁶SO₂R⁹, —SO₂NR⁷R⁸, —NR⁶CONR⁷R⁸,—NR⁶COOR⁹ and —NR⁶SO₂NR⁷R⁸; or (c) a 3 to 8-membered saturated orpartially unsaturated monocyclic heteroaryl, containing 1 or 2heteroatoms selected from O and N, said heteroaryl being optionallysubstituted by 1-5 substituents selected from C₁-C₆ alkyl, C₃-C₈cycloalkyl, halo, oxo, —OR⁶, —NR⁷R⁸, —SR⁶, —SOR⁹, —SO₂R⁹, —COR⁶, —OCOR⁶,—COOR⁶, —NR⁶COR⁶, —CONR⁷R⁸, —NR⁶SO₂R⁹, —SO₂NR⁷R⁸, —NR⁶CONR⁷R⁸, —NR⁶COOR⁹and —NR⁶SO₂NR⁷R⁸; R⁵ is C₁-C₆ alkyl, C₃-C₈ cycloalkyl, halo, —CN, —OR⁶,—NR⁷R⁸, —SR⁶, —SOR⁹, —SO₂R⁹, —COR⁶, —OCOR⁶, —COOR⁶, —NR⁶COR⁶, —CONR⁷R⁸,—NR⁶SO₂R⁹, —SO₂NR⁷R⁸, —NR⁶CONR⁷R⁸, —NR⁶COOR⁹ or —NR⁶SO₂NR⁷R⁸; R⁶ is H,C₁-C₆ alkyl or C₃-C₈ cycloalkyl, said C₁-C₆ alkyl is optionallysubstituted by —NR⁷R⁸ or a 3 to 8-membered saturated or partiallyunsaturated monocyclic heteroaryl, containing 1 or 2 heteroatomsselected from O and N, said heteroaryl being optionally substituted by1-5 substituents selected from C₁-C₆ alkyl, C₃-C₈ cycloalkyl, halo,hydroxy and cyano; R⁷ and R⁸ are each independently H, C₁-C₆ alkyl orC₃-C₈ cycloalkyl or are taken together with the nitrogen atom to whichthey are attached to form a 4-, 5- or 6-membered saturated heterocyclicring containing 1-2 nitrogen atoms or 1 nitrogen and 1 oxygen atom, saidC₁-C₆ alkyl is optionally substituted by C₃-C₈ cycloalkyl, halo,hydroxy, amino, (C₁-C₆ alkyl)amino or di(C₁-C₆ alkyl)amino and saidheterocyclic ring being optionally substituted by one or more C₁-C₆alkyl or C₃-C₈ cycloalkyl groups; R⁹ is C₁-C₆ alkyl or C₃-C₈ cycloalkyl;R¹⁰ is —NHSO₂—R′, —NR″SO₂—R′ or SR′ where R′ and R″ are independentlyhydrogen, C₁-C₆ alkyl, C₃-C₈ cycloalkyl, phenyl, amino, C₁-C₆alkylamino, di(C₁-C₆ alkyl)amino, heterocyclic, —(CH₂)_(n)—W, where W ishydroxy, C₃-C₈ cycloalkyl, phenyl, naphthyl, heterocyclic, 5- or6-membered heteroaryl containing 1-3 N and/or O atoms; wherein each ofsaid alkyl, cycloalkyl, heterocyclic, phenyl, naphthyl or heteroaryl maybe unsubstituted or substituted by phenyl, heteroaryl, heterocyclic,halo, cyano, hydroxy, C₁-C₆ alkyl, C₁-C₆ alkoxy, aryloxy, —SO₂—R′,—NHSO₂—R′, —NR″SO₂—R′ or SR′ where R′ and R″ are independently phenyl,C₁-C₆ alkyl or C₃-C₈ cycloalkyl; R¹¹ and R¹² are each independently H,hydroxy, halo, cyano, C₁-C₆ alkyl or C₃-C₈ cycloalkyl; and, m and n areindependently 0, 1, 2, or
 3. 17. The method of claim 14, wherein thecompound has the structure:

or a pharmaceutically acceptable salt thereof, or a pharmaceuticallyacceptable solvate of said compound or pharmaceutically acceptable salt,wherein: A″ and A′″ are independently C or N, where C may beunsubstituted or substituted by halo or C₁-C₆ alkyl; R¹ is H, cyano orhalo; R² and R^(2′) are independently H, C₁-C₆ alkyl, cyano, C₁-C₆alkoxy, C₁-C₆ alkylthio, or C₃-C₈ cycloalkyl where alkyl, alkoxy, orcycloalkyl is optionally substituted by one or more fluorine atoms; R³is H, C₁-C₄ alkyl, phenyl, naphthyl, 6-membered heteroaryl orheterocyclic containing 1-3 N atoms, a 5-membered heteroaryl orheterocyclic containing either (a) 1-4 N atoms or (b) 1 O or S atom and0-3 N atoms, a 10-membered bicyclic heteroaryl or heterocycliccontaining 1-4 N atoms, a 9-membered bicyclic heteroaryl or heterocycliccontaining either (a) 1-4 N atoms or (b) 1 O or S atom and 0-3 N atoms,or an 8-membered bicyclic heteroaryl or heterocyclic containing (a) 1-4N atoms or (b) 1 O or S atom and 1-3 N atoms or (c) 2 O or S atoms and0-2 N atoms; wherein each of said phenyl, naphthyl, heteroaryl orheterocyclic is optionally substituted by alkyl, 1 substituent —Y—R⁴and/or 1-4 substituents each independently selected from R⁵; Y is abond, —(CH₂)_(m)— or —O—; R⁴ is (a) H, C₁-C₆ alkyl, C₃-C₈ cycloalkyl,halo, oxo, —OR⁶, —NR⁷R⁸, —SR⁶, —SOR⁹, —SO₂R⁹, —COR⁶, —OCOR⁶, —COOR⁶,—NR⁶COR⁶, —CONR⁷R⁸, —NR⁶SO₂R⁹, —SO₂NR⁷R⁸, —NR⁶CONR⁷R⁸, —NR⁶COOR⁹ and—NR⁶SO₂NR⁷R⁸; (b) phenyl or naphthyl, said phenyl and naphthyl beingoptionally substituted with 1-5 substituents selected from C₁-C₆ alkyl,C₃-C₈ cycloalkyl, halo, —CN, —OR⁶, —NR⁷R⁸, —SR⁶, —SOR⁹, —SO₂R⁹, —COR⁶,—OCOR⁶, —COOR⁶, —NR⁶COR⁶, —CONR⁷R⁸, —NR⁶SO₂R⁹, —SO₂NR⁷R⁸, —NR⁶CONR⁷R⁸,—NR⁶COOR⁹ and —NR⁶SO₂NR⁷R⁸; or (c) a 3 to 8-membered saturated orpartially unsaturated monocyclic heteroaryl, containing 1 or 2heteroatoms selected from O and N, said heteroaryl being optionallysubstituted by 1-5 substituents selected from C₁-C₆ alkyl, C₃-C₈cycloalkyl, halo, oxo, —OR⁶, —NR⁷R⁸, —SR⁶, —SOR⁹, —SO₂R⁹, —COR⁶, —OCOR⁶,—COOR⁶, —NR⁶COR⁶, —CONR⁷R⁸, —NR⁶SO₂R⁹, —SO₂NR⁷R⁸, —NR⁶CONR⁷R⁸, —NR⁶COOR⁹and —NR⁶SO₂NR⁷R⁸; R⁵ is C₁-C₆ alkyl, C₃-C₈ cycloalkyl, halo, —CN, —OR⁶,—NR⁷R⁸, —SR⁶, —SOR⁹, —SO₂R⁹, —COR⁶, —OCOR⁶, —COOR⁶, —NR⁶COR⁶, —CONR⁷R⁸,—NR⁶SO₂R⁹, —SO₂NR⁷R⁸, —NR⁶CONR⁷R⁸, —NR⁶COOR⁹ or —NR⁶SO₂NR⁷R⁸; R⁶ is H,C₁-C₆ alkyl or C₃-C₈ cycloalkyl, said C₁-C₆ alkyl is optionallysubstituted by —NR⁷R⁸ or a 3 to 8-membered saturated or partiallyunsaturated monocyclic heteroaryl, containing 1 or 2 heteroatomsselected from O and N, said heteroaryl being optionally substituted by1-5 substituents selected from C₁-C₆ alkyl, C₃-C₈ cycloalkyl, halo,hydroxy and cyano; R⁷ and R⁸ are each independently H, C₁-C₆ alkyl orC₃-C₈ cycloalkyl or are taken together with the nitrogen atom to whichthey are attached to form a 4-, 5- or 6-membered saturated heterocyclicring containing 1-2 nitrogen atoms or 1 nitrogen and 1 oxygen atom, saidC₁-C₆ alkyl is optionally substituted by C₃-C₈ cycloalkyl, halo,hydroxy, amino, (C₁-C₆ alkyl)amino or di(C1-C₆ alkyl)amino and saidheterocyclic ring being optionally substituted by one or more C₁-C₆alkyl or C₃-C₈ cycloalkyl groups; R⁹ is C₁-C₆ alkyl or C₃-C₈ cycloalkyl;R¹⁰ is —NHSO₂—R′, —NR″SO₂—R′ or SR′ where R′ and R″ are independentlyhydrogen, C₁-C₆ alkyl, C₃-C₈ cycloalkyl, phenyl, amino, C₁-C₆alkylamino, di(C1-C₆ alkyl)amino, heterocyclic, —(CH₂)_(n)—W, where W ishydroxy, C₃-C₈ cycloalkyl, phenyl, naphthyl, heterocyclic, 5- or6-membered heteroaryl containing 1-3 N and/or O atoms; wherein each ofsaid alkyl, cycloalkyl, heterocyclic, phenyl, naphthyl or heteroaryl maybe unsubstituted or substituted by phenyl, heteroaryl, heterocyclic,halo, hydroxy, C₁-C₆ alkyl, C₁-C₆ alkoxy, aryloxy, —SO₂—R′, —NHSO₂—R′,—NR″SO₂—R′ or SR′ where R′ and R″ are independently phenyl, C₁-C₆ alkylor C₃-C₈ cycloalkyl; R¹¹ and R¹² are each independently H, hydroxy,halo, cyano, C₁-C₆ alkyl or C₃-C₈ cycloalkyl; and, m and n areindependently 0, 1, 2 or
 3. 18. The method of claim 14, wherein thecompound has the structure:

or a pharmaceutically acceptable salt thereof, or a pharmaceuticallyacceptable solvate of said compound or pharmaceutically acceptable salt,wherein: R¹ is H, cyano or halo; R² and R^(2′) are independently H,C₁-C₆ alkyl, cyano, C₁-C₆ alkoxy, C₁-C₆ alkylthio, or C₃-C₈ cycloalkylwhere alkyl, alkoxy, or cycloalkyl is optionally substituted by one ormore fluorine atoms; R³ is H, C₁-C₄ alkyl, phenyl, naphthyl, 6-memberedheteroaryl or heterocyclic containing 1-3 N atoms, a 5-memberedheteroaryl or heterocyclic containing either (a) 1-4 N atoms or (b) 1 Oor S atom and 0-3 N atoms, a 10-membered bicyclic heteroaryl orheterocyclic containing 1-4 N atoms, a 9-membered bicyclic heteroaryl orheterocyclic containing either (a) 1-4 N atoms or (b) 1 O or S atom and0-3 N atoms, or an 8-membered bicyclic heteroaryl or heterocycliccontaining (a) 1-4 N atoms or (b) 1 O or S atom and 1-3 N atoms or (c) 2O or S atoms and 0-2 N atoms; wherein each of said phenyl, naphthyl,heteroaryl or heterocyclic is optionally substituted by alkyl, 1substituent —Y—R⁴ and/or 1-4 substituents each independently selectedfrom R⁵; Y is a bond, —(CH₂)_(m)— or —O—; R⁴ is (a) H, C₁-C₆ alkyl,C₃-C₈ cycloalkyl, halo, oxo, —OR⁶, —NR⁷R⁸, —SR⁶, —SOR⁹, —SO₂R⁹, —COR⁶,—OCOR⁶, —COOR⁶, —NR⁶COR⁶, —CONR⁷R⁸, —NR⁶SO₂R⁹, —SO₂NR⁷R⁸, —NR⁶CONR⁷R⁸,—NR⁶COOR⁹ and —NR⁶SO₂NR⁷R⁸; (b) phenyl or naphthyl, said phenyl andnaphthyl being optionally substituted with 1-5 substituents selectedfrom C₁-C₆ alkyl, C₃-C₈ cycloalkyl, halo, —CN, —OR⁶, —NR⁷R⁸, —SR⁶,—SOR⁹, —SO₂R⁹, —COR⁶, —OCOR⁶, —COOR⁶, —NR⁶COR⁶, —CONR⁷R⁸, —NR⁶SO₂R⁹,—SO₂NR⁷R⁸, —NR⁶CONR⁷R⁸, —NR⁶COOR⁹ and —NR⁶SO₂NR⁷R⁸; or (c) a 3 to8-membered saturated or partially unsaturated monocyclic heteroaryl,containing 1 or 2 heteroatoms selected from O and N, said heteroarylbeing optionally substituted by 1-5 substituents selected from C₁-C₆alkyl, C₃-C₈ cycloalkyl, halo, oxo, —OR⁶, —NR⁷R⁸, —SR⁶, —SOR⁹, —SO₂R⁹,—COR⁶, —OCOR⁶, —COOR⁶, —NR⁶COR⁶, —CONR⁷R⁸, —NR⁶SO₂R⁹, —SO₂NR⁷R⁸,—NR⁶CONR⁷R⁸, —NR⁶COOR⁹ and —NR⁶SO₂NR⁷R⁸; R⁵ is C₁-C₆ alkyl, C₃-C₈cycloalkyl, halo, —CN, —OR⁶, —NR⁷R⁸, —SR⁶, —SOR⁹, —SO₂R⁹, —COR⁶, —OCOR⁶,—COOR⁶, —NR⁶COR⁶, —CONR⁷R⁸, —NR⁶SO₂R⁹, —SO₂NR⁷R⁸, —NR⁶CONR⁷R⁸, —NR⁶COOR⁹or —NR⁶SO₂NR⁷R⁸; R⁶ is H, C₁-C₆ alkyl or C₃-C₈ cycloalkyl, said C₁-C₆alkyl is optionally substituted by —NR⁷R⁸ or a 3 to 8-membered saturatedor partially unsaturated monocyclic heteroaryl, containing 1 or 2heteroatoms selected from O and N, said heteroaryl being optionallysubstituted by 1-5 substituents selected from C₁-C₆ alkyl, C₃-C₈cycloalkyl, halo, hydroxy and cyano; R⁷ and R⁸ are each independently H,C₁-C₆ alkyl or C₃-C₈ cycloalkyl or are taken together with the nitrogenatom to which they are attached to form a 4-, 5- or 6-membered saturatedheterocyclic ring containing 1-2 nitrogen atoms or 1 nitrogen and 1oxygen atom, said C₁-C₆ alkyl is optionally substituted by C₃-C₈cycloalkyl, halo, hydroxy, amino, (C₁-C₆ alkyl)amino or di(C₁-C₆alkyl)amino and said heterocyclic ring being optionally substituted byone or more C₁-C₆ alkyl or C₃-C₈ cycloalkyl groups; R⁹ is C₁-C₆ alkyl orC₃-C₈ cycloalkyl; R¹⁰ is —NHSO₂—R′, —NR″SO₂—R′ or SR′ where R′ and R″are independently hydrogen, C₁-C₆ alkyl, C₃-C₈ cycloalkyl, phenyl,amino, C₁-C₆ alkylamino, di(C₁-C₆ alkyl)amino, heterocyclic,—(CH₂)_(n)—W, where W is hydroxy, C₃-C₈ cycloalkyl, phenyl, naphthyl,heterocyclic, 5- or 6-membered heteroaryl containing 1-3 N and/or Oatoms; wherein each of said alkyl, cycloalkyl, heterocyclic, phenyl,naphthyl or heteroaryl may be unsubstituted or substituted by phenyl,heteroaryl, heterocyclic, halo, cyano, hydroxy, C₁-C₆ alkyl, C₁-C₆alkoxy, aryloxy, —SO₂—R′, —NHSO₂—R′, —NR″SO₂—R′ or SR′ where R′ and R″are independently phenyl, C₁-C₆ alkyl or C₃-C₈ cycloalkyl; R¹¹ and R¹²are each independently H, hydroxy, halo, cyano, C₁-C₆ alkyl or C₃-C₈cycloalkyl; and, m and n are independently 0, 1, 2 or
 3. 19. The methodof claim 14 wherein the compound has the structure:

or a pharmaceutically acceptable salt thereof, or a pharmaceuticallyacceptable solvate of said compound or pharmaceutically acceptable salt,wherein: A and A′ are independently C or N, where C may be unsubstitutedor substituted by C₁-C₆ alkyl; R and R⁰ are independently selected fromthe group consisting of H, C₁-C₆ alkyl, hydroxy(C₁-C₆ alkyl),phenyl(C₁-C₆ alkyl), and —(CH₂)_(n)—W, where W is C₃-C₈ cycloalkyl,phenyl, naphthyl, 5- or 6-membered heteroaryl or heterocyclic containing1-3 N, S and/or O atoms, —SO₂—R′, —NHSO₂—R′, —NR″SO₂—R′ and SR′, whereR′ and R″ are independently C₁-C₆ alkyl or C₃-C₈ cycloalkyl, amino,C₁-C₆ alkylamino, di(C₁-C₆ alkyl)amino, phenyl, heteroaryl, orheterocyclic; wherein each of said alkyl, cycloalkyl, heterocyclic,phenyl, naphthyl or heteroaryl may be unsubstituted or substituted byphenyl, heteroaryl, heterocyclic, halo, cyano, hydroxy, C₁-C₆ alkyl,C₁-C₆ alkoxy, aryloxy, —SO₂—R′, —CONR′R″, NR′COR″, —NR′CONR′R″,—NR′CO₂R″, —(CH₂)_(n)—SO₂—R′, —NHSO₂—R′, —NR″SO₂—R′ or SR′ where R′ andR″ are independently C₁-C₆ alkyl, C₃-C₈ cycloalkyl, phenyl, amino,hydroxyalkylamino, heterocyclic, or —(CH₂)_(n)—W′, where W is hydroxy,C₃-C₈ cycloalkyl, phenyl, naphthyl, heterocyclic, or 5- or 6-memberedheteroaryl containing 1-3 N, S and/or O atoms; or, R and R⁰ and the Natom to which they are bonded together form a monocyclic or bicyclicheterocyclic ring which may be unsubstituted or substituted by (a) halo,hydroxy, heteroaryl, C₁-C₆ alkyl, C₁-C₆ alkoxy, (C₁-C₆ alkoxy)C₁-C₆alkoxy, aryl(C₁-C₆ alkoxy), aryloxy, amino, aminoacyl, C₁-C₆alkylaminoacyl, arylalkylaminoacyl, di(C₁-C₆ alkyl)aminoacyl, —SO₂—R′,—SO₂—NR″—(CH₂)_(n)—W, —NHSO₂—R′, —NR″SO₂—R′ or SR′ where R′ and R″ isindependently amino, C₁-C₆ alkylamino, di(C1-C₆ alkyl)amino, C₁-C₆ alkylor C₃-C₈ cycloalkyl, or (b) —(CH₂)_(n)—W, where W is C₃-C₈ cycloalkyl,phenyl, naphthyl, heterocyclic, 5- or 6-membered heteroaryl containing1-3 N atoms, —SO₂—R′, —NHSO₂—R′, —NR″SO₂—R′ or SR′, where R′ and R″ isindependently alkyl or cycloalkyl; wherein each of said phenyl, aryl, orheteroaryl may be unsubstituted or substituted by halo, C₁-C₆ alkyl,C₁-C₆ alkoxy, cyano, or hydroxy; R¹ is halo; R² and R^(2′) areindependently H, C₁-C₆ alkyl, cyano, C₁-C₆ alkoxy, C₁-C₆ alkylthio, orC₃-C₈ cycloalkyl where alkyl, alkoxy, or cycloalkyl is optionallysubstituted by one or more fluorine atoms; and, n is 0, 1, 2 or
 3. 20.The method of claim 14 wherein the compound has the structure:

or a pharmaceutically acceptable salt thereof, or a pharmaceuticallyacceptable solvate of said compound or pharmaceutically acceptable salt,wherein: A, A′, A″ and A′″ are independently C or N, where C may beunsubstituted or substituted by halo or C₁-C₆ alkyl; R¹ is H, cyano orhalo; R² and R^(2′) are independently H, C₁-C₆ alkyl, cyano, C₁-C₆alkoxy, C₁-C₆ alkylthio, or C₃-C₈ cycloalkyl where alkyl, alkoxy, orcycloalkyl is optionally substituted by one or more fluorine atoms; R¹⁰is —NHSO₂—R′, —NR″SO₂—R′ or SR′ where R′ and R″ is independently C₁-C₆alkyl or C₃-C₈ cycloalkyl; and, R¹¹ and R¹² are each independently H,hydroxy, halo, cyano, C₁-C₆ alkyl or C₃-C₈ cycloalkyl.
 21. The method ofclaim 14 wherein the compound has the structure:

or a pharmaceutically acceptable salt thereof, or a pharmaceuticallyacceptable solvate of said compound or pharmaceutically acceptable salt,wherein: A″ and A′″ are independently C or N, where C may beunsubstituted or substituted by halo or C₁-C₆ alkyl; R¹ is H, cyano orhalo; R² and R^(2′) are independently H, C₁-C₆ alkyl, cyano, C₁-C₆alkoxy, C₁-C₆ alkylthio, or C₃-C₈ cycloalkyl where alkyl, alkoxy, orcycloalkyl is optionally substituted by one or more fluorine atoms; R¹⁰is —NHSO₂—R′, —NR″SO₂—R′ or SR′ where R′ and R″ are independentlyhydrogen, C₁-C₆ alkyl, C₃-C₈ cycloalkyl, phenyl, amino, C₁-C₆alkylamino, di(C₁-C₆ alkyl)amino, heterocyclic, —(CH₂)_(n)—W, where W ishydroxy, C₃-C₈ cycloalkyl, phenyl, naphthyl, heterocyclic, 5- or6-membered heteroaryl containing 1-3 N and/or O atoms; wherein each ofsaid alkyl, cycloalkyl, heterocyclic, phenyl, naphthyl or heteroaryl maybe unsubstituted or substituted by phenyl, heteroaryl, heterocyclic,halo, cyanohydroxy, C₁-C₆ alkyl, C₁-C₆ alkoxy, aryloxy, —SO₂—R′,—NHSO₂—R′, —NR″SO₂—R′ or SR′ where R′ and R″ are independently phenyl,C₁-C₆ alkyl or C₃-C₈ cycloalkyl; R¹¹ and R¹² are each independently H,hydroxy, halo, cyano, C₁-C₆ alkyl or C₃-C₈ cycloalkyl; and, m and n areindependently 0, 1, 2 or
 3. 22. The method of claim 14 wherein thecompound has the structure:

or a pharmaceutically acceptable salt thereof, or a pharmaceuticallyacceptable solvate of said compound or pharmaceutically acceptable salt,wherein: R¹ is H, cyano or halo; R² and R^(2′) are independently H,C₁-C₆ alkyl, cyano, C₁-C₆ alkoxy, C₁-C₆ alkylthio, or C₃-C₈ cycloalkylwhere alkyl, alkoxy, or cycloalkyl is optionally substituted by one ormore fluorine atoms; R¹⁰ is —NHSO₂—R′, —NR″SO₂—R′ or SR′ where R′ and R″are independently hydrogen, C₁-C₈ alkyl, C₃-C₈ cycloalkyl, phenyl,amino, C₁-C₆ alkylamino, di(C₁-C₆ alkyl)amino, heterocyclic,—(CH₂)_(n)—W, where W is hydroxy, C₃-C₈ cycloalkyl, phenyl, naphthyl,heterocyclic, 5- or 6-membered heteroaryl containing 1-3 N and/or Oatoms; wherein each of said alkyl, cycloalkyl, heterocyclic, phenyl,naphthyl or heteroaryl may be unsubstituted or substituted by phenyl,heteroaryl, heterocyclic, halo, cyano, hydroxy, C₁-C₆ alkyl, C₁-C₆alkoxy, aryloxy, —SO₂—R′, —NHSO₂—R′, —NR″SO₂—R′ or SR′ where R′ and R″are independently phenyl, C₁-C₆ alkyl or C₃-C₈ cycloalkyl; and, n is 0,1, 2 or
 3. 23. The method of claim 14 wherein the compound is selectedfrom the group consisting of:4-({2-[ethyl(ethylsulfonyl)amino]benzyl}amino)-6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)-phenyl]-N-methyl-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;4-({2-[ethyl(ethylsulfonyl)amino]benzyl}amino)-6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-N-methyl-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-4-({2-[(ethylsulfonyl)(methyl)amino]benzyl}amino)-N-methyl-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-4-[2-(4-hydroxyphenyl)ethyl]amino}-N-methyl-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-N-methyl-4-[(2-methylpropyl)amino]-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;4-({5-chloro-2-[methyl(methylsulfonyl)amino]benzyl}amino)-6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-N-methyl-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-4-({5-fluoro-2-[methyl(methylsulfonyl)amino]benzyl}amino)-N-methyl-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-4-({2-fluoro-[methyl(methylsulfonyl)amino]benzyl}amino)-N-methyl-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-4-({2-[ethyl(methylsulfonyl)amino]benzyl}amino)-N-methyl-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;4-[(cyclopentylmethyl)amino]-6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-N-methyl-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-N-methyl-4-({5-methyl-2-[methyl(methylsul-fonyl)amino]benzyl}amino)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;4-({2-[ethyl(methylsulfonyl)amino]benzyl}amino)-6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoro-ethyl)phenyl]-N-methyl-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;4-({2-[(ethylsulfonyl)(methyl)amino]benzyl}amino)-6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-N-methyl-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-4-({5-fluoro-2-[methyl(methylsulfonyl)amino]benzyl}amino)-N-methyl-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;4-({5-chloro-2-[methyl(methylsulfonyl)amino]benzyl}amino)-6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-N-methyl-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-N-methyl-4-[(2-methylpropyl)amino]-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;4-[(cyclopentylmethyl)amino]-6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-N-methyl-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-4-({2-fluoro-6-[methyl(methylsulfonyl)-amino]benzyl}amino)-N-methyl-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-N-methyl-4-({2-[methyl(methylsulfonyl)amino]benzyl}-amino)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-N-methyl-4-({2-[methyl(methylsulfonyl)-amino]benzyl}amino)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-N-methyl-4-({5-methyl-2-[methyl(methylsulfonyl)amino]-benzyl}amino)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-N-methyl-4-({2-[methyl(phenylsulfonyl)-amino]benzyl}amino)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-N-methyl-4-[(2-{4-[(phenylsufonyl)amino]-phenyl}ethyl)-amino]-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-4-({2-[(2-hydroxyethyl)(methylsulfonyl)-amino]benzyl}amino)-N-methyl-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-4-({2-[methyl(phenylsulfonyl)amino]benzyl}-amino)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-4-({2-[(2-hydroxyethyl)(methylsulfonyl)-amino]benzyl}amino)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-4-({4-hydroxy-2-[methyl(methylsulfonyl)amino]benzyl}-amino)-N-methyl-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-4-({4-hydroxy-2-[methyl(methylsulfonyl)amino]benzyl}-amino)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-4-({5-hydroxy-2-[methyl(methylsulfonyl)amino]benzyl}-amino)-N-methyl-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-4-[(2-[(3-hydroxyphenyl)sulfonyl](methyl)-amino)benzyl)amino]-N-methyl-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-4-({4-hydroxy-2-[methyl(methylsulfonyl)-amino]benzyl}amino)-N-methyl-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;4-({2-[ethyl(methylsulfonyl)amino]-5-hydroxybenzyl}amino)-6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-N-methyl-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-4-({5-hydroxy-2-[methyl(phenylsulfonyl)-amino]benzyl}amino)-N-methyl-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;4-({2-[ethyl(phenylsulfonyl)amino]-5-hydroxybenzyl}amino)-6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-N-methyl-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;6-(2-cyclopropyl-5-fluoro-4-hydroxyphenyl)-N-methyl-4-({2-[methyl(methylsulfonyl)amino]-benzyl}amino)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-N-methyl-4-{[(1R)-1-(2-[methyl(methylsulfonyl)amino]-phenyl}ethyl]amino}-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-N-methyl-4-{[(1S)-1-{2-[methyl(methylsulfonyl)-amino]phenyl}ethyl]amino}-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-4-({2-[methyl(phenylsulfonyl)amino]benzyl}amino)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-4-({4-hydroxy-2-[methyl(methylsulfonyl)-amino]benzyl}amino)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-4-({5-hydroxy-2-[methyl(phenylsulfonyl)-amino]benzyl}amino)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;4-({2-[ethyl(phenylsulfonyl)amino]-5-hydroxybenzyl}amino)-6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-N-methyl-4-[({3-[methyl(phenylsulfonyl)-amino]pyrazin-2-yl}methyl)amino]-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;4-[({3-[ethyl(methylsulfonyl)amino]pyrazin-2-yl}methyl)amino]-6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-N-methyl-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;N-ethyl-4-[({3-[ethyl(methylsulfonyl)amino]pyrazin-2-yl}methyl)amino]-6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;6-(2-cyclopropyl-5-fluoro-4-hydroxyphenyl)-4-({2-[methyl(methylsulfonyl)amino]benzyl}amino)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-N-methyl-4-[({4-[methyl(methylsulfonyl)-amino]pyridin-3-yl}methyl)amino]-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;6-(2-cyclopropyl-5-fluoro-4-hydroxyphenyl)-N-methyl-4-[({2-[methyl(methylsulfonyl)amino]-pyridin-3-yl}methyl)amino]-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-4-({5-methoxy-2-[methyl(methylsulfonyl)-amino]benzyl}amino)-N-methyl-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-N-methyl-4-[({3-[methyl(methylsulfonyl)amino]pyrazin-2-yl}methyl)amino]-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;4-[({2-[ethyl(methylsulfonyl)amino]pyridin-3-yl}methyl)amino]-6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-N-methyl-4-[({2-[methyl(methylsulfonyl)-amino]pyridin-3-yl}methyl)amino]-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-4-({5-hydroxy-2-[methyl(pyridin-3-ylsulfonyl)amino]benzyl}amino)-N-methyl-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-N-methyl-4-[({3-[methyl(methylsulfonyl)-amino]pyridin-2-yl}methyl)amino]-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-4-({2-[methyl(methylsulfonyl)amino]benzyl}amino)-N-(6-methylpyridin-3-yl)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;6-(5-fluor-hydroxy-2-(2,2,2-trifluoroethyl)phenyl)-N-methyl-4-((1,3,3-trimethylureido)benzyl)-amino)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;6-(5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl)-N-methyl-4-((2-(N-methyl-1H-pyrazole-4-sulfonamido)benzyl)amino)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;4-((2-N,1-dimethyl-1H-imidazole-4-sulfonamido)benzyl)amido)-6-(5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl)-N-methyl-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-4-[(2-[(2-methoxyethyl)sulfonyl]-(methyl)amino)benzyl)amino]-N-methyl-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-4-({2-[methyl(pyridin-3-ylsulfonyl)amino]benzyl}amino)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-4-[({2-[methyl(methylsulfonyl)amino]pyridin-3-yl}methyl)amino]-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;4-[({2-[ethyl(methylsulfonyl)amino]pyridin-3-yl}methyl)amino]-6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-N-methyl-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-N-methyl-4-{[2-(sulfamoylmethyl)benzyl]-amino}-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-4-{[2-(methyl{[6-(morpholin-4-yl)pyridin-3-yl]sulfonyl}amino)benzyl]amino}-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-4-[2-(methyl{[3-(morpholin-4-yl)propyl]sulfonyl]amino)benzyl}amino)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-N-methyl-4-[({5-methyl-2-[methyl(methyl-sulfonyl)amino]pyridin-3-yl}methyl)amino]-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-N-methyl-4-({2-[methyl(pyridin-3-ylsulfonyl)amino]benzyl}amino)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-N-methyl-4-[(2-{methyl[(6-methylpyridin-3-yl)sulfonyl]amino}benzyl)amino]-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-4-[(2-{methyl[(6-methylpyridin-3-yl)sulfonyl]amino}benzyl)amino]-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;4-[({5-chloro-2-[ethyl(methylsulfonyl)amino]pyridin-3-yl}methyl)amino]-6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;4-[({5-chloro-2-[methyl(methylsulfonyl)amino]pyridin-3-yl}methyl)amino]-6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-N-methyl-4-({2-[methyl(sulfamoyl)amino]benzyl}amino)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;6-(5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl)-4-((N-(2-hydroxyethyl)sulfamoyl)(methyl)-aminobenzyl)amino)-N-methyl-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-N-{6-[(2-hydroxyethyl)amino]pyridin-3-yl}-4-({5-hydroxy-2-[methyl(methylsulfonyl)amino]benzyl}amino)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-4-({2-[methyl(methylsulfonyl)amino]benzyl}amino)-N-(6-methylpyridin-3-yl)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-4-({2-[methyl(methylsulfonyl)-amino]benzyl}amino)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-4-[({5-fluoro-2-[methyl(methylsulfonyl)-amino]pyridin-3-yl}methyl)amino]-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;4-[({2-[ethyl(methylsulfonyl)amino]-5-fluoropyridin-3-yl}methyl)amino]-6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;4-[({3-[ethyl(methylsulfonyl)amino]pyrazin-2-yl}methyl)amino]-6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-4-({5-methyl-2-[methyl(methylsulfonyl)-amino]benzyl}amino)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;4-((2-(N-ethylethylsulfonamido)benzyl)amino)-6-(5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;4-((2-(N-ethylmethylsulfonamido)-5-fluorobenzyl)amino)-6-(5-fluoro-4-hydroxy-2-(2,2,2-trifluoro-ethyl)phenyl)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;4-((5-chloro-2-(N-ethylmethylsulfonamido)benzyl)amino)-6-(5-fluoro-4-hydroxy-2-(2,2,2-trifluoro-ethyl)phenyl)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;6-(5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl)-4-((2-(N-methylethyl-sulfonamido)benzyl)-amino)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;6-(5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl)-4-(((5-methyl-2-(N-methylmethylsulfonamido)pyridin-3-yl)methyl)amino)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;4-[({2-[ethyl(methylsulfonyl)amino]-5-methylpyridin-3-yl}methyl)amino]-6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-4-({5-fluoro-2-[methyl(methylsulfonyl)-amino]benzyl}amino)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;4-({5-chloro-2-[methyl(methylsulfonyl)amino]benzyl}amino)-6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;4-({2-[ethyl(methylsulfonyl)amino]benzyl}amino)-6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)-phenyl]-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;4-({2-[ethyl(methylsulfonyl)amino]-5-methylbenzyl}amino)-6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-4-({5-hydroxy-2-[methyl(methylsulfonyl)-amino]benzyl}amino)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-N-methyl-4-((2-(N-methylmethylsulfonamido)benzyl)-amino)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide;6-(5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl)-N-methyl-4-((2-(N-methylmethylsulfonamido)benzyl)amino)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide;6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-4-((2-(N-methylphenylsulfonamido)benzyl)amino)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide;6-(5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl)-4-((2-(N-methylphenylsulfonamido)-benzyl)amino)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide;6-(5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl)-4-((5-hydroxy-2-(N-methylmethylsulfonamido)benzyl)amino)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide;6-(5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl)-4-((2-(N-methylmethylsulfonamido)benzyl)amino)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide;6-(5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl)-4-((5-hydroxy-2-(N-methylmethylsulfonamido)benzyl)amino)-N-(6-((2-hydroxyethyl)amino)pyridin-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide;6-(5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl)-N-methyl-4-(((3-(N-methylmethylsulfonamido)pyrazin-2-yl)methyl)amino)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide;6-(5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl)-4-((2-(N-(2-hydroxyethyl)methyl-sulfonamido)benzyl)amino)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide;6-(5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl)-4-((2-(N-(2-hydroxyethyl)methylsulfonamido)benzyl)amino)-N-methyl-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide;4-((2-(N-ethylmethylsulfonamido)benzyl)amino)-6-(5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)-phenyl)-N-methyl-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide;4-((5-fluoro-2-(N-methylmethylsulfonamido)benzyl)amino)-6-(5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl)-N-methyl-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide;4-((2-(N-ethylphenylsulfonamido)-5-hydroxybenzyl)amino)-6-(5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl)-N-methyl-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide;4-((2-(N-methylphenylsulfonamido)-5-hydroxybenzyl)amino)-6-(5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl)-N-methyl-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide;4-((2-(N-ethylphenylsulfonamido)-5-hydroxybenzyl)amino)-6-(5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide;4-((2-(N-methylphenylsulfonamido)-5-hydroxybenzyl)amino)-6-(5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide;6-(5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl)-N-methyl-4-((2-(methyl(sulfamoyl)amino)-benzyl)amino)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide;6-(5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl)-N-methyl-4-((2-(methyl(N-methylsulfamoyl)amino)benzyl)amino)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide;4-[4-(7, 8-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl]-3-ethylphenolformate;3-ethyl-4-[4-(3-phenoxyazetidin-1-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl]phenolformate;3-ethyl-4-{4-[6-(4-methyl-1H-imidazol-1-yl)-3,4-dihydroisoquinolin-2(1H)-yl]-1H-pyrazolo[4,3-c]pyridin-6-yl}phenolformate;3-ethyl-4-{4-[6-(2-methoxyethoxy)-3,4-dihydroisoquinolin-2(1H)-yl]-1H-pyrazolo[4,3-c]pyridin-6-yl}phenolformate;1-[6-(2-ethyl-4-hydroxyphenyl)-1H-pyrazolo[4,3-c]pyridin-4-yl]-3-methylazetidin-3-olformate;2-[6-(2-ethyl-4-hydroxyphenyl)-1H-pyrazolo[4,3-c]pyridin-4-yl]-N-[2-(pyrrolidin-1-yl)ethyl]-1,2,3,4-tetrahydroisoquinoline-7-sulfonamideformate;N-benzyl-2-[6-(2-ethyl-4-hydroxyphenyl)-1H-pyrazolo[4,3-c]pyridin-4-yl]-1,2,3,4-tetrahydroisoquinoline-5-carboxamideformate;4-{4-[7-(benzyloxy)-6-methoxy-3,4-dihydroisoquinolin-2(1H)-yl]-1H-pyrazolo[4,3-c]pyridin-6-yl}-3-ethylphenolformate;4-[4-(5-chloro-3,4-dihydroisoquinolin-2(1H)-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl]-3-ethylphenolformate;4-chloro-3-({1-[6-(2-ethyl-4-hydroxyphenyl)-1H-pyrazolo[4,3-c]pyridin-4-yl]azetidin-3-yl}oxy)benzonitrileformate;3-ethyl-4-[4-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl]phenolformate;3-ethyl-4-[4-(8-methoxy-3,4-dihydroisoquinolin-2(1H)-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl]phenolformate;N-{2-[6-(2-ethyl-4-hydroxyphenyl)-1H-pyrazolo[4,3-c]pyridin-4-yl]-1,2,3,4-tetrahydroisoquinolin-5-yl}methanesulfonamideformate;4-(4-{[2-(biphenyl-4-yl)ethyl]amino}-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-ethylphenolformate;N-[2-({[6-(2-ethyl-4-hydroxyphenyl)-1H-pyrazolo[4,3-c]pyridin-4-yl]amino}methyl)phenyl]-N-methylmethanesulfonamidehydrochloride;1-[6-(2-ethyl-4-hydroxyphenyl)-1H-pyrazolo[4,3-c]pyridin-4-yl]-N,N-dimethylpyrrolidine-3-sulfonamide (racemic);N-[2-({[6-(2-ethyl-4-hydroxyphenyl)-1H-pyrazolo[4,3-c]pyridin-4-yl]amino}methyl)-3-methylphenyl]-N-methylmethanesufonamidediethylamine salt;3-ethyl-4-[4-(4-methoxypipendin-1-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl]phenoldiethylamine salt;N-[2-({[2-(3,4-dimethoxyphenyl)ethyl][6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-pyrazolo[4,3-c]pyridin-4-yl]amino}methyl)phenyl]-N-methylmethanesulfonamidehydrochloride;N-[2-({[6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-pyrazolo[4,3-c]pyridin-4-yl](2-{4-[(methylsulfonyl)amino]phenyl}ethyl)amino}methyl)phenyl]-N-methylmethanesulfonamidehydrochloride;N-[2-({[6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-pyrazolo[4,3-c]pyridin-4-yl]amino}methyl)-phenyl]-N-methylmethanesulfonamide;N-[2-({[6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-pyrazolo[4,3-c]pyridin-4-yl]amino}methyl)-4-methylphenyl]-N-methylmethanesulfonamidehydrochloride;N-[4-chloro-2-({[6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-pyrazolo[4,3-c]pyridin-4-yl]amino}methyl)phenyl]-N-methylmethanesulfonamidehydrochloride;N-[2-({[6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-pyrazolo[4,3-c]pyridin-4-yl]amino}methyl)-3-fluorophenyl]-N-methylmethanesulfonamidehydrochloride;N-[2-({[6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-pyrazolo[4,3-c]pyridin-4-yl]amino}methyl)-phenyl]-N-methylethanesulfonamidehydrochloride;N-ethyl-N-[2-({[6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-pyrazolo[4,3-c]pyridin-4-yl]amino}-methyl)phenyl]ethanesulfonamidehydrochloride;N-[2-({[6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-pyrazolo[4,3-c]pyridin-4-yl]amino}methyl)phenyl]-N-propylmethanesulfonamide;N-ethyl-N-[2-({[6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-pyrazolo[4,3-c]pyridin-4-yl]amino}-methyl)phenyl]methanesulfonamide;N-butyl-N-[2-({[6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-pyrazolo[4,3-c]pyridin-4-yl]amino}-methyl)phenyl]methanesulfonamide;N-[2-({[6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-pyrazolo[4,3-c]pyridin-4-yl][2-(morpholin-4-yl)ethyl]amino}methyl)phenyl]-N-methylmethanesulfonamide;N-[2-({[6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-pyrazolo[4,3-c]pyridin-4-yl][2-(morpholin-4-yl)ethyl]amino}methyl)phenyl]-N-methylmethanesulfonamide;N-ethyl-N-[2-({[6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-pyrazolo[4,3-c]pyridin-4-yl](methyl)-amino}methyl)-4-methylphenyl]methanesulfonamide;N-[2-({ethyl[6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-pyrazolo[4,3-c]pyridin-4-yl]amino}methyl)-4-methylphenyl]-N-methylmethanesulfonamide;N-[2-({[6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-pyrazolo[4,3-c]pyridin-4-yl](propyl)amino}-methyl)-4-methylphenyl]-N-methylmethanesulfonamide;N-ethyl-N-[2-({[6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-pyrazolo[4,3-c]pyridin-4-yl](methyl)amino}methyl)phenyl]methanesulfonamidehydrochloride;N-[2-({[6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-pyrazolo[4,3-c]pyridin-4-yl](methyl)amino}-methyl)phenyl]-N-methylmethanesulfonamidehydrochloride;N-[2-({[6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-pyrazolo[4,3-c]pyridin-4-yl]amino}methyl)phenyl]-N-(2-hydroxyethyl)methanesulfonamide;N-{2-[({6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-1H-pyrazolo[4,3-c]pyridin-4-yl}amino)methyl]phenyl}-N-methylmethanesulfonamide;N-(2-{[{6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-1H-pyrazolo[4,3-c]pyridin-4-yl}(methyl)amino]methyl}phenyl)-N-methylmethanesulfonamide;N-{2-[({6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-1H-pyrazolo[4,3-c]pyridin-4-yl}amino)methyl]-4-methylphenyl}-N-methylmethanesulfonamide;4-{4-[(cyclopropylmethyl)amino]-1H-pyrazolo[3,4-d]pyrimidin-6-yl}-2-fluoro-5-(2,2,2-trifluoroethyl)phenol;4-{4-[(2-cyclopropylethyl)amino]-1H-pyrazolo[3,4-d]pyrimidin-6-yl}-2-fluoro-5-(2,2,2-trifluoroethyl)phenol;2-fluoro-4-{4-[(2-methylpropyl)amino]-1H-pyrazolo[3,4-d]pyrimidin-6-yl}-5-(2,2,2-trifluoro-ethyl)phenol;4-[4-(butylamino)-1H-pyrazolo[3,4-d]pyrimidin-6-yl]-2-fluoro-5-(2,2,2-trifluoroethyl)phenol;N-[2-({[6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]amino}methyl)-phenyl]-N-methylmethanesulfonamidehydrochloride;N-(2-(((6-(2-ethyl-4-hydroxy-6-methylphenyl)-1H-pyrazolo[4,3-c]pyridin-4-yl)amino)methyl)-phenyl)-N-methylmethanesulfonamide;N-[2-({[6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-3-(1H-imidazol-2-yl)-1H-pyrazolo[4,3-c]pyridin-4-yl]amino}methyl)phenyl]-N-methylmethanesulfonamide;N-[2-({[3-(4,5-dimethyl-1H-imidazol-2-yl)-6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-pyrazolo[4,3-c]pyridin-4-yl]amino}methyl)phenyl]-N-methylmethanesulfonamide;N-[2-({[6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-3-(4-methyl-1H-imidazol-2-yl)-1H-pyrazolo[4,3-c]pyridin-4-yl]amino}methyl)phenyl]-N-methylmethanesulfonamide;4-[3-(5-benzyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yl)-4-{[2-(methylsulfanyl)ethyl]-amino}-1H-pyrazolo[4,3-c]pyridin-6-yl]-2-fluoro-5-(2,2,2-trifluoroethyl)phenol;N-[2-({[6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-3-(1H-pyrazol-1-yl)-1H-pyrazolo[4,3-c]pyridin-4-yl]amino}methyl)phenyl]-N-methylmethanesulfonamide;N-{2-[({6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-3-(1H-pyrazol-1-yl)-1H-pyrazolo[4,3-c]pyridin-4-yl}amino)methyl]phenyl}-N-methylmethanesulfonamide;N-{2-[({6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-3-(5-methyl-4H-1,2,4-triazol-3-yl)-1H-pyrazolo[4,3-c]pyridin-4-yl}amino)methyl]phenyl}-N-methylmethanesulfonamide;N-[2-({[6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-3-(5-methyl-4H-1,2,4-triazol-3-yl)-1H-pyrazolo[4,3-c]pyridin-4-yl]amino}methyl)phenyl]-N-methylmethanesulfonamide;N-{2-[({6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-3-[5-(6-methylpyridin-3-yl)-4H-1,2,4-triazol-3-yl]-1H-pyrazolo[4,3-c]pyridin-4-yl}amino)methyl]phenyl}-N-methylmethanesulfonamide;4-(5-{6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-4-({5-hydroxy-2-[methyl(methyl-sulfonyl)amino]benzyl}amino)-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-4H-1,2,4-triazol-3-yl)piperidine-1-carboxamide;N-(2-[(6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-3-{5-[1-(pyrrolidin-1-ylacetyl)pipendin-4-yl]-4H-1,2,4-triazol-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino]methyl}phenyl)-N-methyl-methanesulfonamide;N-{2-[({6-[5-fluoro-4-hydroxy-2-(2, 2, 2-trifluoroethyl)phenyl]-3-(4, 5,6, 7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl}amino)methyl]-4-hydroxyphenyl}-N-methylmethanesulfonamide;N-{2-[({3-(5-acetyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yl)-6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-4-yl}amino)methyl]-4-hydroxyphenyl}-N-methylmethanesulfonamide;N-[2-(dimethylamino)ethyl]-2-{6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-4-({5-hydroxy-2-[methyl(methylsulfonyl)amino]benzyl}amino)-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxamide; and,4-(3-(5-benzyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yl)-4-((3-hydroxy-2-methylpropyl)-amino)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-2-fluoro-5-(2,2,2-trifluoroethyl)phenol.24. The method of claim 15, wherein the compound has the structure:

or a pharmaceutically acceptable salt thereof, or a pharmaceuticallyacceptable solvate of said compound or pharmaceutically acceptable salt,wherein: A, A″ and A′″ are independently C or N, where C may beunsubstituted or substituted by halo or C₁-C₆ alkyl; R¹ is H, cyano orhalo; R² and R^(2′) are independently H, C₁-C₆ alkyl, cyano, C₁-C₆alkoxy, C₁-C₆ alkylthio, or C₃-C₈ cycloalkyl where alkyl, alkoxy, orcycloalkyl is optionally substituted by one or more fluorine atoms; R³is H, C₁-C₄ alkyl, phenyl, naphthyl, 6-membered heteroaryl orheterocyclic containing 1-3 N atoms, a 5-membered heteroaryl orheterocyclic containing either (a) 1-4 N atoms or (b) 1 O or S atom and0-3 N atoms, a 10-membered bicyclic heteroaryl or heterocycliccontaining 1-4 N atoms, a 9-membered bicyclic heteroaryl or heterocycliccontaining either (a) 1-4 N atoms or (b) 1 O or S atom and 0-3 N atoms,or an 8-membered bicyclic heteroaryl or heterocyclic containing (a) 1-4N atoms or (b) 1 O or S atom and 1-3 N atoms or (c) 2 O or S atoms and0-2 N atoms; wherein each of said phenyl, naphthyl, heteroaryl orheterocyclic is optionally substituted by alkyl, 1 substituent —Y—R⁴and/or 1-4 substituents each independently selected from R⁵; Y is abond, —(CH₂)_(m)— or —O—; R⁴ is (a) H, C₁-C₆ alkyl, C₃-C₈ cycloalkyl,halo, oxo, —OR⁶, —NR⁷R⁸, —SR⁶, —SOR⁹, —SO₂R⁹, —COR⁶, —OCOR⁶, —COOR⁶,—NR⁶COR⁶, —CONR⁷R⁸, —NR⁶SO₂R⁹, —SO₂NR⁷R⁸, —NR⁶CONR⁷R⁸, —NR⁶COOR⁹ and—NR⁶SO₂NR⁷R⁸; (b) phenyl or naphthyl, said phenyl and naphthyl beingoptionally substituted with 1-5 substituents selected from C₁-C₆ alkyl,C₃-C₈ cycloalkyl, halo, —CN, —OR⁶, —NR⁷R⁸, —SR⁶, —SOR⁹, —SO₂R⁹, —COR⁶,—OCOR⁶, —COOR⁶, —NR⁶COR⁶, —CONR⁷R⁸, —NR⁶SO₂R⁹, —SO₂NR⁷R⁸, —NR⁶CONR⁷R⁸,—NR⁶COOR⁹ and —NR⁶SO₂NR⁷R⁸; or (c) a 3 to 8-membered saturated orpartially unsaturated monocyclic heteroaryl, containing 1 or 2heteroatoms selected from O and N, said heteroaryl being optionallysubstituted by 1-5 substituents selected from C₁-C₆ alkyl, C₃-C₈cycloalkyl, halo, oxo, —OR⁶, —NR⁷R⁸, —SR⁶, —SOR⁹, —SO₂R⁹, —COR⁶, —OCOR⁶,—COOR⁶, —NR⁶COR⁶, —CONR⁷R⁸, —NR⁶SO₂R⁹, —SO₂NR⁷R⁸, —NR⁶CONR⁷R⁸, —NR⁶COOR⁹and —NR⁶SO₂NR⁷R⁸; R⁵ is C₁-C₆ alkyl, C₃-C₈ cycloalkyl, halo, —CN, —OR⁶,—NR⁷R⁸, —SR⁶, —SOR⁹, —SO₂R⁹, —COR⁶, —OCOR⁶, —COOR⁶, —NR⁶COR⁶, —CONR⁷R⁸,—NR⁶SO₂R⁹, —SO₂NR⁷R⁸, —NR⁶CONR⁷R⁸, —NR⁶COOR⁹ or —NR⁶SO₂NR⁷R⁸; R⁶ is H,C₁-C₆ alkyl or C₃-C₈ cycloalkyl, said C₁-C₆ alkyl is optionallysubstituted by —NR⁷R⁸ or a 3 to 8-membered saturated or partiallyunsaturated monocyclic heteroaryl, containing 1 or 2 heteroatomsselected from O and N, said heteroaryl being optionally substituted by1-5 substituents selected from C₁-C₆ alkyl, C₃-C₈ cycloalkyl, halo,hydroxy and cyano; R⁷ and R⁸ are each independently H, C₁-C₆ alkyl orC₃-C₈ cycloalkyl or are taken together with the nitrogen atom to whichthey are attached to form a 4-, 5- or 6-membered saturated heterocyclicring containing 1-2 nitrogen atoms or 1 nitrogen and 1 oxygen atom, saidC₁-C₆ alkyl is optionally substituted by C₃-C₈ cycloalkyl, halo,hydroxy, amino, (C₁-C₆ alkyl)amino or di(C1-C₆ alkyl)amino and saidheterocyclic ring being optionally substituted by one or more C₁-C₆alkyl or C₃-C₈ cycloalkyl groups; R⁹ is C₁-C₆ alkyl or C₃-C₈ cycloalkyl;R¹⁰ is —NHSO₂—R′, —NR″SO₂—R′ or SR′ where R′ and R″ are independentlyhydrogen, C₁-C₆ alkyl, C₃-C₈ cycloalkyl, phenyl, amino, C₁-C₆alkylamino, di(C₁-C₆ alkyl)amino, heterocyclic, —(CH₂)_(n)—W, where W ishydroxy, C₃-C₈ cycloalkyl, phenyl, naphthyl, heterocyclic, 5- or6-membered heteroaryl containing 1-3 N and/or O atoms; wherein each ofsaid alkyl, cycloalkyl, heterocyclic, phenyl, naphthyl or heteroaryl maybe unsubstituted or substituted by phenyl, heteroaryl, heterocyclic,halo, cyano, hydroxy, C₁-C₆ alkyl, C₁-C₆ alkoxy, aryloxy, —SO₂—R′,—NHSO₂—R′, —NR″SO₂—R′ or SR′ where R′ and R″ are independently phenyl,C₁-C₆ alkyl or C₃-C₈ cycloalkyl; R¹¹ and R¹² are each independently H,hydroxy, halo, cyano, C₁-C₆ alkyl or C₃-C₈ cycloalkyl; and, m and n areindependently 0, 1, 2, or
 3. 25. The method of claim 15, wherein thecompound has the structure:

or a pharmaceutically acceptable salt thereof, or a pharmaceuticallyacceptable solvate of said compound or pharmaceutically acceptable salt,wherein: A″ and A′″ are independently C or N, where C may beunsubstituted or substituted by halo or C₁-C₆ alkyl; R¹ is H, cyano orhalo; R² and R^(2′) are independently H, C₁-C₆ alkyl, cyano, C₁-C₆alkoxy, C₁-C₆ alkylthio, or C₃-C₈ cycloalkyl where alkyl, alkoxy, orcycloalkyl is optionally substituted by one or more fluorine atoms; R³is H, C₁-C₄ alkyl, phenyl, naphthyl, 6-membered heteroaryl orheterocyclic containing 1-3 N atoms, a 5-membered heteroaryl orheterocyclic containing either (a) 1-4 N atoms or (b) 1 O or S atom and0-3 N atoms, a 10-membered bicyclic heteroaryl or heterocycliccontaining 1-4 N atoms, a 9-membered bicyclic heteroaryl or heterocycliccontaining either (a) 1-4 N atoms or (b) 1 O or S atom and 0-3 N atoms,or an 8-membered bicyclic heteroaryl or heterocyclic containing (a) 1-4N atoms or (b) 1 O or S atom and 1-3 N atoms or (c) 2 O or S atoms and0-2 N atoms; wherein each of said phenyl, naphthyl, heteroaryl orheterocyclic is optionally substituted by alkyl, 1 substituent —Y—R⁴and/or 1-4 substituents each independently selected from R⁵; Y is abond, —(CH₂)_(m)— or —O—; R⁴ is (a) H, C₁-C₆ alkyl, C₃-C₈ cycloalkyl,halo, oxo, —OR⁶, —NR⁷R⁸, —SR⁶, —SOR⁹, —SO₂R⁹, —COR⁶, —OCOR⁶, —COOR⁶,—NR⁶COR⁶, —CONR⁷R⁸, —NR⁶SO₂R⁹, —SO₂NR⁷R⁸, —NR⁶CONR⁷R⁸, —NR⁶COOR⁹ and—NR⁶SO₂NR⁷R⁸; (b) phenyl or naphthyl, said phenyl and naphthyl beingoptionally substituted with 1-5 substituents selected from C₁-C₆ alkyl,C₃-C₈ cycloalkyl, halo, —CN, —OR⁶, —NR⁷R⁸, —SR⁶, —SOR⁹, —SO₂R⁹, —COR⁶,—OCOR⁶, —COOR⁶, —NR⁶COR⁶, —CONR⁷R⁸, —NR⁶SO₂R⁹, —SO₂NR⁷R⁸, —NR⁶CONR⁷R⁸,—NR⁶COOR⁹ and —NR⁶SO₂NR⁷R⁸; or (c) a 3 to 8-membered saturated orpartially unsaturated monocyclic heteroaryl, containing 1 or 2heteroatoms selected from O and N, said heteroaryl being optionallysubstituted by 1-5 substituents selected from C₁-C₆ alkyl, C₃-C₈cycloalkyl, halo, oxo, —OR⁶, —NR⁷R⁸, —SR⁶, —SOR⁹, —SO₂R⁹, —COR⁶, —OCOR⁶,—COOR⁶, —NR⁶COR⁶, —CONR⁷R⁸, —NR⁶SO₂R⁹, —SO₂NR⁷R⁸, —NR⁶CONR⁷R⁸, —NR⁶COOR⁹and —NR⁶SO₂NR⁷R⁸; R⁵ is C₁-C₆ alkyl, C₃-C₈ cycloalkyl, halo, —CN, —OR⁶,—NR⁷R⁸, —SR⁶, —SOR⁹, —SO₂R⁹, —COR⁶, —OCOR⁶, —COOR⁶, —NR⁶COR⁶, —CONR⁷R⁸,—NR⁶SO₂R⁹, —SO₂NR⁷R⁸, —NR⁶CONR⁷R⁸, —NR⁶COOR⁹ or —NR⁶SO₂NR⁷R⁸; R⁶ is H,C₁-C₆ alkyl or C₃-C₈ cycloalkyl, said C₁-C₆ alkyl is optionallysubstituted by —NR⁷R⁸ or a 3 to 8-membered saturated or partiallyunsaturated monocyclic heteroaryl, containing 1 or 2 heteroatomsselected from O and N, said heteroaryl being optionally substituted by1-5 substituents selected from C₁-C₆ alkyl, C₃-C₈ cycloalkyl, halo,hydroxy and cyano; R⁷ and R⁸ are each independently H, C₁-C₆ alkyl orC₃-C₈ cycloalkyl or are taken together with the nitrogen atom to whichthey are attached to form a 4-, 5- or 6-membered saturated heterocyclicring containing 1-2 nitrogen atoms or 1 nitrogen and 1 oxygen atom, saidC₁-C₆ alkyl is optionally substituted by C₃-C₈ cycloalkyl, halo,hydroxy, amino, (C₁-C₆ alkyl)amino or di(C₁-C₆ alkyl)amino and saidheterocyclic ring being optionally substituted by one or more C₁-C₆alkyl or C₃-C₈ cycloalkyl groups; R⁹ is C₁-C₆ alkyl or C₃-C₈ cycloalkyl;R¹⁰ is —NHSO₂—R′, —NR″SO₂—R′ or SR′ where R′ and R″ are independentlyhydrogen, C₁-C₆ alkyl, C₃-C₈ cycloalkyl, phenyl, amino, C₁-C₆alkylamino, di(C₁-C₆ alkyl)amino, heterocyclic, —(CH₂)_(n)—W, where W ishydroxy, C₃-C₈ cycloalkyl, phenyl, naphthyl, heterocyclic, 5- or6-membered heteroaryl containing 1-3 N and/or O atoms; wherein each ofsaid alkyl, cycloalkyl, heterocyclic, phenyl, naphthyl or heteroaryl maybe unsubstituted or substituted by phenyl, heteroaryl, heterocyclic,halo, hydroxy, C₁-C₆ alkyl, C₁-C₆ alkoxy, aryloxy, —SO₂—R′, —NHSO₂—R′,—NR″SO₂—R′ or SR′ where R′ and R″ are independently phenyl, C₁-C₆ alkylor C₃-C₈ cycloalkyl; R¹¹ and R¹² are each independently H, hydroxy,halo, cyano, C₁-C₆ alkyl or C₃-C₈ cycloalkyl; and, m and n areindependently 0, 1, 2 or
 3. 26. The method of claim 15, wherein thecompound has the structure:

or a pharmaceutically acceptable salt thereof, or a pharmaceuticallyacceptable solvate of said compound or pharmaceutically acceptable salt,wherein: R¹ is H, cyano or halo; R² and R^(2′) are independently H,C₁-C₆ alkyl, cyano, C₁-C₆ alkoxy, C₁-C₆ alkylthio, or C₃-C₈ cycloalkylwhere alkyl, alkoxy, or cycloalkyl is optionally substituted by one ormore fluorine atoms; R³ is H, C₁-C₄ alkyl, phenyl, naphthyl, 6-memberedheteroaryl or heterocyclic containing 1-3 N atoms, a 5-memberedheteroaryl or heterocyclic containing either (a) 1-4 N atoms or (b) 1 Oor S atom and 0-3 N atoms, a 10-membered bicyclic heteroaryl orheterocyclic containing 1-4 N atoms, a 9-membered bicyclic heteroaryl orheterocyclic containing either (a) 1-4 N atoms or (b) 1 O or S atom and0-3 N atoms, or an 8-membered bicyclic heteroaryl or heterocycliccontaining (a) 1-4 N atoms or (b) 1 O or S atom and 1-3 N atoms or (c) 2O or S atoms and 0-2 N atoms; wherein each of said phenyl, naphthyl,heteroaryl or heterocyclic is optionally substituted by alkyl, 1substituent —Y—R⁴ and/or 1-4 substituents each independently selectedfrom R⁵; Y is a bond, —(CH₂)_(m)— or —O—; R⁴ is (a) H, C₁-C₆ alkyl,C₃-C₈ cycloalkyl, halo, oxo, —OR⁶, —NR⁷R⁸, —SR⁶, —SOR⁹, —SO₂R⁹, —COR⁶,—OCOR⁶, —COOR⁶, —NR⁶COR⁶, —CONR⁷R⁸, —NR⁶SO₂R⁹, —SO₂NR⁷R⁸, —NR⁶CONR⁷R⁸,—NR⁶COOR⁹ and —NR⁶SO₂NR⁷R⁸; (b) phenyl or naphthyl, said phenyl andnaphthyl being optionally substituted with 1-5 substituents selectedfrom C₁-C₆ alkyl, C₃-C₈ cycloalkyl, halo, —CN, —OR⁶, —NR⁷R⁸, —SR⁶,—SOR⁹, —SO₂R⁹, —COR⁶, —OCOR⁶, —COOR⁶, —NR⁶COR⁶, —CONR⁷R⁸, —NR⁶SO₂R⁹,—SO₂NR⁷R⁸, —NR⁶CONR⁷R⁸, —NR⁶COOR⁹ and —NR⁶SO₂NR⁷R⁸; or (c) a 3 to8-membered saturated or partially unsaturated monocyclic heteroaryl,containing 1 or 2 heteroatoms selected from O and N, said heteroarylbeing optionally substituted by 1-5 substituents selected from C₁-C₆alkyl, C₃-C₈ cycloalkyl, halo, oxo, —OR⁶, —NR⁷R⁸, —SR⁶, —SOR⁹, —SO₂R⁹,—COR⁶, —OCOR⁶, —COOR⁶, —NR⁶COR⁶, —CONR⁷R⁸, —NR⁶SO₂R⁹, —SO₂NR⁷R⁸,—NR⁶CONR⁷R⁸, —NR⁶COOR⁹ and —NR⁶SO₂NR⁷R⁸; R⁵ is C₁-C₆ alkyl, C₃-C₈cycloalkyl, halo, —CN, —OR⁶, —NR⁷R⁸, —SR⁶, —SOR⁹, —SO₂R⁹, —COR⁶, —OCOR⁶,—COOR⁶, —NR⁶COR⁶, —CONR⁷R⁸, —NR⁶SO₂R⁹, —SO₂NR⁷R⁸, —NR⁶CONR⁷R⁸, —NR⁶COOR⁹or —NR⁶SO₂NR⁷R⁸; R⁶ is H, C₁-C₆ alkyl or C₃-C₈ cycloalkyl, said C₁-C₆alkyl is optionally substituted by —NR⁷R⁸ or a 3 to 8-membered saturatedor partially unsaturated monocyclic heteroaryl, containing 1 or 2heteroatoms selected from O and N, said heteroaryl being optionallysubstituted by 1-5 substituents selected from C₁-C₆ alkyl, C₃-C₈cycloalkyl, halo, hydroxy and cyano; R⁷ and R⁸ are each independently H,C₁-C₆ alkyl or C₃-C₈ cycloalkyl or are taken together with the nitrogenatom to which they are attached to form a 4-, 5- or 6-membered saturatedheterocyclic ring containing 1-2 nitrogen atoms or 1 nitrogen and 1oxygen atom, said C₁-C₆ alkyl is optionally substituted by C₃-C₈cycloalkyl, halo, hydroxy, amino, (C₁-C₆ alkyl)amino or di(C₁-C₆alkyl)amino and said heterocyclic ring being optionally substituted byone or more C₁-C₆ alkyl or C₃-C₈ cycloalkyl groups; R⁹ is C₁-C₆ alkyl orC₃-C₈ cycloalkyl; R¹⁰ is —NHSO₂—R′, —NR″SO₂—R′ or SR′ where R′ and R″are independently hydrogen, C₁-C₆ alkyl, C₃-C₈ cycloalkyl, phenyl,amino, C₁-C₆ alkylamino, di(C₁-C₆ alkyl)amino, heterocyclic,—(CH₂)_(n)—W′, where W is hydroxy, C₃-C₈ cycloalkyl, phenyl, naphthyl,heterocyclic, 5- or 6-membered heteroaryl containing 1-3 N and/or Oatoms; wherein each of said alkyl, cycloalkyl, heterocyclic, phenyl,naphthyl or heteroaryl may be unsubstituted or substituted by phenyl,heteroaryl, heterocyclic, halo, cyano, hydroxy, C₁-C₆ alkyl, C₁-C₆alkoxy, aryloxy, —SO₂—R′, —NHSO₂—R′, —NR″SO₂—R′ or SR′ where R′ and R″are independently phenyl, C₁-C₆ alkyl or C₃-C₈ cycloalkyl; R¹¹ and R¹²are each independently H, hydroxy, halo, cyano, C₁-C₆ alkyl or C₃-C₈cycloalkyl; and, m and n are independently 0, 1, 2 or
 3. 27. The methodof claim 15 wherein the compound has the structure:

or a pharmaceutically acceptable salt thereof, or a pharmaceuticallyacceptable solvate of said compound or pharmaceutically acceptable salt,wherein: A and A′ are independently C or N, where C may be unsubstitutedor substituted by C₁-C₆ alkyl; R and R⁰ are independently selected fromthe group consisting of H, C₁-C₆ alkyl, hydroxy(C₁-C₆ alkyl),phenyl(C₁-C₆ alkyl), and —(CH₂)_(n)—W, where W is C₃-C₈ cycloalkyl,phenyl, naphthyl, 5- or 6-membered heteroaryl or heterocyclic containing1-3 N, S and/or O atoms, —SO₂—R′, —NHSO₂—R′, —NR″SO₂—R′ and SR′, whereR′ and R″ are independently C₁-C₆ alkyl or C₃-C₈ cycloalkyl, amino,C₁-C₆ alkylamino, di(C₁-C₆ alkyl)amino, phenyl, heteroaryl, orheterocyclic; wherein each of said alkyl, cycloalkyl, heterocyclic,phenyl, naphthyl or heteroaryl may be unsubstituted or substituted byphenyl, heteroaryl, heterocyclic, halo, cyano, hydroxy, C₁-C₆ alkyl,C₁-C₆ alkoxy, aryloxy, —SO₂—R′, —CONR′R″, NR′COR″, —NR′CONR′R″,—NR′CO₂R″, —(CH₂)_(n)—SO₂—R′, —NHSO₂—R′, —NR″SO₂—R′ or SR′ where R′ andR″ are independently C₁-C₆ alkyl, C₃-C₈ cycloalkyl, phenyl, amino,hydroxyalkylamino, heterocyclic, or —(CH₂)_(n)—W′, where W′ is hydroxy,C₃-C₈ cycloalkyl, phenyl, naphthyl, heterocyclic, or 5- or 6-memberedheteroaryl containing 1-3 N, S and/or O atoms; or, R and R⁰ and the Natom to which they are bonded together form a monocyclic or bicyclicheterocyclic ring which may be unsubstituted or substituted by (a) halo,hydroxy, heteroaryl, C₁-C₆ alkyl, C₁-C₆ alkoxy, (C₁-C₆ alkoxy)C₁-C₆alkoxy, aryl(C₁-C₆ alkoxy), aryloxy, amino, aminoacyl, C₁-C₆alkylaminoacyl, arylalkylaminoacyl, di(C₁-C₆ alkyl)aminoacyl, —SO₂—R′,—SO₂—NR″—(CH₂)_(n)—W, —NHSO₂—R′, —NR″SO₂—R′ or SR′ where R′ and R″ isindependently amino, C₁-C₆ alkylamino, di(C₁-C₆ alkyl)amino, C₁-C₆ alkylor C₃-C₈ cycloalkyl, or (b) —(CH₂)_(n)—W, where W is C₃-C₈ cycloalkyl,phenyl, naphthyl, heterocyclic, 5- or 6-membered heteroaryl containing1-3 N atoms, —SO₂—R′, —NHSO₂—R′, —NR″SO₂—R′ or SR′, where R′ and R″ isindependently alkyl or cycloalkyl; wherein each of said phenyl, aryl, orheteroaryl may be unsubstituted or substituted by halo, C₁-C₆ alkyl,C₁-C₆ alkoxy, cyano, or hydroxy; R¹ is halo; R² and R^(2′) areindependently H, C₁-C₆ alkyl, cyano, C₁-C₆ alkoxy, C₁-C₆ alkylthio, orC₃-C₈ cycloalkyl where alkyl, alkoxy, or cycloalkyl is optionallysubstituted by one or more fluorine atoms; and, n is 0, 1, 2 or
 3. 28.The method of claim 15 wherein the compound has the structure:

or a pharmaceutically acceptable salt thereof, or a pharmaceuticallyacceptable solvate of said compound or pharmaceutically acceptable salt,wherein: A, A′, A″ and A′″ are independently C or N, where C may beunsubstituted or substituted by halo or C₁-C₆ alkyl; R¹ is H, cyano orhalo; R² and R^(2′) are independently H, C₁-C₆ alkyl, cyano, C₁-C₆alkoxy, C₁-C₆ alkylthio, or C₃-C₈ cycloalkyl where alkyl, alkoxy, orcycloalkyl is optionally substituted by one or more fluorine atoms; R¹⁰is —NHSO₂—R′, —NR″SO₂—R′ or SR′ where R′ and R″ is independently C₁-C₆alkyl or C₃-C₈ cycloalkyl; and, R¹¹ and R¹² are each independently H,hydroxy, halo, cyano, C₁-C₆ alkyl or C₃-C₈ cycloalkyl.
 29. The method ofclaim 15 wherein the compound has the structure:

or a pharmaceutically acceptable salt thereof, or a pharmaceuticallyacceptable solvate of said compound or pharmaceutically acceptable salt,wherein: A″ and A′″ are independently C or N, where C may beunsubstituted or substituted by halo or C₁-C₆ alkyl; R¹ is H, cyano orhalo; R² and R^(2′) are independently H, C₁-C₆ alkyl, cyano, C₁-C₆alkoxy, C₁-C₆ alkylthio, or C₃-C₈ cycloalkyl where alkyl, alkoxy, orcycloalkyl is optionally substituted by one or more fluorine atoms; R¹⁰is —NHSO₂—R′, —NR″SO₂—R′ or SR′ where R′ and R″ are independentlyhydrogen, C₁-C₆ alkyl, C₃-C₈ cycloalkyl, phenyl, amino, C₁-C₆alkylamino, di(C₁-C₆ alkyl)amino, heterocyclic, —(CH₂)_(n)—W, where W ishydroxy, C₃-C₈ cycloalkyl, phenyl, naphthyl, heterocyclic, 5- or6-membered heteroaryl containing 1-3 N and/or O atoms; wherein each ofsaid alkyl, cycloalkyl, heterocyclic, phenyl, naphthyl or heteroaryl maybe unsubstituted or substituted by phenyl, heteroaryl, heterocyclic,halo, cyanohydroxy, C₁-C₆ alkyl, C₁-C₆ alkoxy, aryloxy, —SO₂—R′,—NHSO₂—R′, —NR″SO₂—R′ or SR′ where R′ and R″ are independently phenyl,C₁-C₆ alkyl or C₃-C₈ cycloalkyl; R¹¹ and R¹² are each independently H,hydroxy, halo, cyano, C₁-C₆ alkyl or C₃-C₈ cycloalkyl; and, m and n areindependently 0, 1, 2 or
 3. 30. The method of claim 15 wherein thecompound has the structure:

or a pharmaceutically acceptable salt thereof, or a pharmaceuticallyacceptable solvate of said compound or pharmaceutically acceptable salt,wherein: R¹ is H, cyano or halo; R² and R^(2′) are independently H,C₁-C₆ alkyl, cyano, C₁-C₆ alkoxy, C₁-C₆ alkylthio, or C₃-C₈ cycloalkylwhere alkyl, alkoxy, or cycloalkyl is optionally substituted by one ormore fluorine atoms; R¹⁰ is —NHSO₂—R′, —NR″SO₂—R′ or SR′ where R′ and R″are independently hydrogen, C₁-C₆ alkyl, C₃-C₈ cycloalkyl, phenyl,amino, C₁-C₆ alkylamino, di(C₁-C₆ alkyl)amino, heterocyclic,—(CH₂)_(n)—W, where W is hydroxy, C₃-C₈ cycloalkyl, phenyl, naphthyl,heterocyclic, 5- or 6-membered heteroaryl containing 1-3 N and/or Oatoms; wherein each of said alkyl, cycloalkyl, heterocyclic, phenyl,naphthyl or heteroaryl may be unsubstituted or substituted by phenyl,heteroaryl, heterocyclic, halo, cyano, hydroxy, C₁-C₆ alkyl, C₁-C₆alkoxy, aryloxy, —SO₂—R′, —NHSO₂—R′, —NR″SO₂—R′ or SR′ where R′ and R″are independently phenyl, C₁-C₆ alkyl or C₃-C₈ cycloalkyl; and, n is 0,1, 2 or
 3. 31. The method of claim 15 wherein the compound is selectedfrom the group consisting of:4-({2-[ethyl(ethylsulfonyl)amino]benzyl}amino)-6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)-phenyl]-N-methyl-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;4-({2-[ethyl(ethylsulfonyl)amino]benzyl}amino)-6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-N-methyl-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-4-({2-[(ethylsulfonyl)(methyl)amino]benzyl}amino)-N-methyl-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-4-{[2-(4-hydroxyphenyl)ethyl]amino}-N-methyl-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-N-methyl-4-[(2-methylpropyl)amino]-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;4-({5-chloro-2-[methyl(methylsulfonyl)amino]benzyl}amino)-6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-N-methyl-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-4-({5-fluoro-2-[methyl(methylsulfonyl)amino]benzyl}amino)-N-methyl-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-4-({2-fluoro-6-[methyl(methylsulfonyl)amino]benzyl}amino)-N-methyl-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-4-({2-[ethyl(methylsulfonyl)amino]benzyl}amino)-N-methyl-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;4-[(cyclopentylmethyl)amino]-6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-N-methyl-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-N-methyl-4-({5-methyl-2-[methyl(methylsul-fonyl)amino]benzyl}amino)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;4-({2-[ethyl(methylsulfonyl)amino]benzyl}amino)-6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoro-ethyl)phenyl]-N-methyl-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;4-({2-[(ethylsulfonyl)(methyl)amino]benzyl}amino)-6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-N-methyl-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-4-({5-fluoro-2-[methyl(methylsulfon-yl)amino]benzyl}amino)-N-methyl-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;4-({5-chloro-2-[methyl(methylsulfonyl)amino]benzyl}amino)-6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-N-methyl-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-N-methyl-4-[(2-methylpropyl)amino]-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;4-[(cyclopentylmethyl)amino]-6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-N-methyl-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-4-({2-fluoro-6-[methyl(methylsulfonyl)-amino]benzyl}amino)-N-methyl-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-N-methyl-4-({2-[methyl(methylsulfonyl)amino]benzyl}-amino)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-N-methyl-4-({2-[methyl(methylsulfonyl)-amino]benzyl}amino)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-N-methyl-4-({5-methyl-2-[methyl(methylsulfonyl)amino]-benzyl}amino)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-N-methyl-4-({2-[methyl(phenylsulfonyl)-amino]benzyl}amino)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-N-methyl-4-[(2-{4-[(phenylsufonyl)amino]-phenyl}ethyl)-amino]-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-4-({2-[(2-hydroxyethyl)(methylsulfonyl)-amino]benzyl}amino)-N-methyl-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-4-({2-[methyl(phenylsulfonyl)amino]benzyl}-amino)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-4-({2-[(2-hydroxyethyl)(methylsulfonyl)-amino]benzyl}amino)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-4-({4-hydroxy-2-[methyl(methylsulfonyl)amino]benzyl}-amino)-N-methyl-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-4-({4-hydroxy-2-[methyl(methylsulfonyl)amino]benzyl}-amino)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-4-({5-hydroxy-2-[methyl(methylsulfonyl)amino]benzyl}-amino)-N-methyl-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-4-[(2-{[(3-hydroxyphenyl)sulfonyl](methyl)-amino}benzyl)amino]-N-methyl-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-4-({4-hydroxy-2-[methyl(methylsulfonyl)-amino]benzyl}amino)-N-methyl-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;4-({2-[ethyl(methylsulfonyl)amino]-5-hydroxybenzyl}amino)-6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-N-methyl-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-4-({5-hydroxy-2-[methyl(phenylsulfonyl)-amino]benzyl}amino)-N-methyl-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;4-({2-[ethyl(phenylsulfonyl)amino]-5-hydroxybenzyl}amino)-6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-N-methyl-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;6-(2-cyclopropyl-5-fluoro-4-hydroxyphenyl)-N-methyl-4-({2-[methyl(methylsulfonyl)amino]-benzyl}amino)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-N-methyl-4-{[(1R)-1-{2-[methyl(methylsulfonyl)amino]-phenyl}ethyl]amino}-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-N-methyl-4-{[(1S)-1-{2-[methyl(methylsulfonyl)-amino]phenyl}ethyl]amino}-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-4-({2-[methyl(phenylsulfonyl)amino]benzyl}amino)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-4-({4-hydroxy-2-[methyl(methylsulfonyl)-amino]benzyl}amino)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-4-({5-hydroxy-2-[methyl(phenylsulfonyl)-amino]benzyl}amino)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;4-({2-[ethyl(phenylsulfonyl)amino]-5-hydroxybenzyl}amino)-6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-N-methyl-4-[({3-[methyl(phenylsulfonyl)-amino]pyrazin-2-yl}methyl)amino]-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;4-[({3-[ethyl(methylsulfonyl)amino]pyrazin-2-yl}methyl)amino]-6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-N-methyl-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;N-ethyl-4-[({3-[ethyl(methylsulfonyl)amino]pyrazin-2-yl}methyl)amino]-6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;6-(2-cyclopropyl-5-fluoro-4-hydroxyphenyl)-4-({2-[methyl(methylsulfonyl)amino]benzyl}amino)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-N-methyl-4-[({4-[methyl(methylsulfonyl)-amino]pyridin-3-yl}methyl)amino]-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;6-(2-cyclopropyl-5-fluoro-4-hydroxyphenyl)-N-methyl-4-[({2-[methyl(methylsulfonyl)amino]-pyridin-3-yl}methyl)amino]-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-4-({5-methoxy-2-[methyl(methylsulfonyl)-amino]benzyl}amino)-N-methyl-1H-pyrazolo[4,3-C]pyridine-3-carboxamide;6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-N-methyl-4-[({3-[methyl(methylsulfonyl)amino]pyrazin-2-yl}methyl)amino]-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;4-[({2-[ethyl(methylsulfonyl)amino]pyridin-3-yl}methyl)amino]-6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-N-methyl-4-[({2-[methyl(methylsulfonyl)-amino]pyridin-3-yl}methyl)amino]-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-4-({5-hydroxy-2-[methyl(pyridin-3-ylsulfonyl)amino]benzyl}amino)-N-methyl-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-N-methyl-4-[({3-[methyl(methylsulfonyl)-amino]pyridin-2-yl}methyl)amino]-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-4-({2-[methyl(methylsulfonyl)amino]benzyl}amino)-N-(6-methylpyridin-3-yl)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;6-(5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl)-N-methyl-4-((1,3,3-trimethylureido)benzyl)-amino)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;6-(5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl)-N-methyl-4-((2-(N-methyl-1H-pyrazole-4-sulfonamido)benzyl)amino)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;4-((2-N,1-dimethyl-1H-imidazole-4-sulfonamido)benzyl)amido)-6-(5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl)-N-methyl-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-4-[(2-[(2-methoxyethyl)sulfonyl]-(methyl)amino)benzyl)amino]-N-methyl-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-4-({2-[methyl(pyridin-3-ylsulfonyl)amino]benzyl}amino)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-4-[({2-[methyl(methylsulfonyl)amino]pyridin-3-yl}methyl)amino]-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;4-[({2-[ethyl(methylsulfonyl)amino]pyridin-3-yl}methyl)amino]-6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-N-methyl-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-N-methyl-4-{[2-(sulfamoylmethyl)benzyl]-amino}-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-4-{[2-(methyl{[6-(morpholin-4-yl)pyridin-3-yl]sulfonyl}amino)benzyl]amino}-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-4-{[2-(methyl{[3-(morpholin-4-yl)propyl]sulfonyl}amino)benzyl]amino}-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-N-methyl-4-[({5-methyl-2-[methyl(methyl-sulfonyl)amino]pyridin-3-yl}methyl)amino]-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-N-methyl-4-({2-[methyl(pyridin-3-ylsulfonyl)amino]benzyl}amino)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-N-methyl-4-[(2-methyl[(6-methylpyridin-3-yl)sulfonyl]amino)benzyl)amino]-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-4-[(2-methyl[(6-methylpyridin-3-yl)sulfonyl]amino)benzyl)amino]-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;4-[({5-chloro-2-[ethyl(methylsulfonyl)amino]pyridin-3-yl}methyl)amino]-6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;4-[({5-chloro-2-[methyl(methylsulfonyl)amino]pyridin-3-yl}methyl)amino]-6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-N-methyl-4-({2-[methyl(sulfamoyl)amino]benzyl}amino)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;6-(5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl)-4-((N-(2-hydroxyethyl)sulfamoyl)(methyl)-aminobenzyl)amino)-N-methyl-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-N-{6-[(2-hydroxyethyl)amino]pyridin-3-yl}-4-({5-hydroxy-2-[methyl(methylsulfonyl)amino]benzyl}amino)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-4-({2-[methyl(methylsulfonyl)amino]benzyl}amino)-N-(6-methylpyridin-3-yl)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-4-({2-[methyl(methylsulfonyl)-amino]benzyl}amino)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-4-[({5-fluoro-2-[methyl(methylsulfonyl)-amino]pyridin-3-yl}methyl)amino]-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;4-[({2-[ethyl(methylsulfonyl)amino]-5-fluoropyridin-3-yl}methyl)amino]-6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;4-[({3-[ethyl(methylsulfonyl)amino]pyrazin-2-yl}methyl)amino]-6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-4-({5-methyl-2-[methyl(methylsulfonyl)-amino]benzyl}amino)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;4-((2-(N-ethylethylsulfonamido)benzyl)amino)-6-(5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;4-((2-(N-ethylmethylsulfonamido)-5-fluorobenzyl)amino)-6-(5-fluoro-4-hydroxy-2-(2,2,2-trifluoro-ethyl)phenyl)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;4-((5-chloro-2-(N-ethylmethylsulfonamido)benzyl)amino)-6-(5-fluoro-4-hydroxy-2-(2,2,2-trifluoro-ethyl)phenyl)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;6-(5-fluor-hydroxy-2-(2,2,2-trifluoroethyl)phenyl)-4-((2-(N-methylethyl-sulfonamido)benzyl)-amino)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;6-(5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl)-4-(((5-methyl-2-(N-methylmethylsulfonamido)pyridin-3-yl)methyl)amino)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;4-[({2-[ethyl(methylsulfonyl)amino]-5-methylpyridin-3-yl}methyl)amino]-6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-4-({5-fluoro-2-[methyl(methylsulfonyl)-amino]benzyl}amino)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;4-({5-chloro-2-[methyl(methylsulfonyl)amino]benzyl}amino)-6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;4-({2-[ethyl(methylsulfonyl)amino]benzyl}amino)-6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)-phenyl]-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;4-({2-[ethyl(methylsulfonyl)amino]-5-methylbenzyl}amino)-6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-4-({5-hydroxy-2-[methyl(methylsulfonyl)-amino]benzyl}amino)-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-N-methyl-4-((2-(N-methylmethylsulfonamido)benzyl)-amino)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide;6-(5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl)-N-methyl-4-((2-(N-methylmethylsulfonamido)benzyl)amino)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide;6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-4-((2-(N-methylphenylsulfonamido)benzyl)amino)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide;6-(5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl)-4-((2-(N-methylphenylsulfonamido)-benzyl)amino)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide;6-(5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl)-4-((5-hydroxy-2-(N-methylmethylsulfonamido)benzyl)amino)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide;6-(5-fluor-hydroxy-2-(2,2,2-trifluoroethyl)phenyl)-4-((2-(N-methylmethylsulfon-amido)benzyl)amino)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide;6-(5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl)-4-((5-hydroxy-2-(N-methylmethylsulfonamido)benzyl)amino)-N-(6-((2-hydroxyethyl)amino)pyridin-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide;6-(5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl)-N-methyl-4-(((3-(N-methylmethylsulfonamido)pyrazin-2-yl)methyl)amino)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide;6-(5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl)-4-((2-(N-(2-hydroxyethyl)methyl-sulfonamido)benzyl)amino)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide;6-(5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl)-4-((2-(N-(2-hydroxyethyl)methylsulfonamido)benzyl)amino)-N-methyl-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide;4-((2-(N-ethylmethylsulfonamido)benzyl)amino)-6-(5-fluoro-hydroxy-2-(2,2,2-trifluoroethyl)-phenyl)-N-methyl-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide;4-((5-fluoro-2-(N-methylmethylsulfonamido)benzyl)amino)-6-(5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl)-N-methyl-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide;4-((2-(N-ethylphenylsulfonamido)-5-hydroxybenzyl)amino)-6-(5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl)-N-methyl-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide;4-((2-(N-methylphenylsulfonamido)-5-hydroxybenzyl)amino)-6-(5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl)-N-methyl-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide;4-((2-(N-ethylphenylsulfonamido)-5-hydroxybenzyl)amino)-6-(5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide;4-((2-(N-methylphenylsulfonamido)-5-hydroxybenzyl)amino)-6-(5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide;6-(5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl)-N-methyl-4-((2-(methyl(sulfamoyl)amino)-benzyl)amino)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide;6-(5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl)-N-methyl-4-((2-(methyl(N-methylsulfamoyl)amino)benzyl)amino)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide;4-[4-(7, 8-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl]-3-ethylphenolformate;3-ethyl-4-[4-(3-phenoxyazetidin-1-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl]phenolformate;3-ethyl-4-{4-[6-(4-methyl-1H-imidazol-1-yl)-3,4-dihydroisoquinolin-2(1H)-yl]-1H-pyrazolo[4,3-c]pyridin-6-yl}phenolformate;3-ethyl-4-{4-[6-(2-methoxyethoxy)-3,4-dihydroisoquinolin-2(1H)-yl]-1H-pyrazolo[4,3-c]pyridin-6-yl}phenolformate;1-[6-(2-ethyl-4-hydroxyphenyl)-1H-pyrazolo[4,3-c]pyridin-4-yl]-3-methylazetidin-3-olformate;2-[6-(2-ethyl-4-hydroxyphenyl)-1H-pyrazolo[4,3-c]pyridin-4-yl]-N-[2-(pyrrolidin-1-yl)ethyl]-1,2,3,4-tetrahydroisoquinoline-7-sulfonamideformate;N-benzyl-2-[6-(2-ethyl-4-hydroxyphenyl)-1H-pyrazolo[4,3-c]pyridin-4-yl]-1,2, 3, 4-tetrahydroisoquinoline-5-carboxamide formate;4-{4-[7-(benzyloxy)-6-methoxy-3,4-dihydroisoquinolin-2(1H)-yl]-1H-pyrazolo[4,3-c]pyridin-6-yl}-3-ethylphenolformate;4-[4-(5-chloro-3,4-dihydroisoquinolin-2(1H)-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl]-3-ethylphenolformate;4-chloro-3-({1-[6-(2-ethyl-4-hydroxyphenyl)-1H-pyrazolo[4,3-c]pyridin-4-yl]azetidin-3-yl}oxy)benzonitnleformate;3-ethyl-4-[4-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl]phenolformate;3-ethyl-4-[4-(8-methoxy-3,4-dihydroisoquinolin-2(1H)-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl]phenolformate;N-{2-[6-(2-ethyl-4-hydroxyphenyl)-1H-pyrazolo[4,3-c]pyridin-4-yl]-1,2,3,4-tetrahydroisoquinolin-5-yl}methanesulfonamideformate;4-(4-{[2-(biphenyl-4-yl)ethyl]amino}-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-ethylphenolformate;N-[2-({[6-(2-ethyl-4-hydroxyphenyl)-1H-pyrazolo[4,3-c]pyridin-4-yl]amino}methyl)phenyl]-N-methylmethanesulfonamidehydrochloride;1-[6-(2-ethyl-4-hydroxyphenyl)-1H-pyrazolo[4,3-c]pyridin-4-yl]-N,N-dimethylpyrrolidine-3-sulfonamide (racemic);N-[2-({[6-(2-ethyl-4-hydroxyphenyl)-1H-pyrazolo[4,3-c]pyridin-4-yl]amino}methyl)-3-methylphenyl]-N-methylmethanesufonamidediethylamine salt;3-ethyl-4-[4-(4-methoxypipendin-1-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl]phenoldiethylamine salt;N-[2-({[2-(3,4-dimethoxyphenyl)ethyl][6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-pyrazolo[4,3-c]pyridin-4-yl]amino}methyl)phenyl]-N-methylmethanesulfonamidehydrochloride;N-[2-({[6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-pyrazolo[4,3-c]pyridin-4-yl](2-{4-[(methylsulfonyl)amino]phenyl}ethyl)amino}methyl)phenyl]-N-methylmethanesulfonamidehydrochloride;N-[2-({[6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-pyrazolo[4,3-c]pyridin-4-yl]amino}methyl)-phenyl]-N-methylmethanesulfonamide;N-[2-({[6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-pyrazolo[4,3-c]pyridin-4-yl]amino}methyl)-4-methylphenyl]-N-methylmethanesulfonamidehydrochloride;N-[4-chloro-2-({[6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-pyrazolo[4,3-c]pyridin-4-yl]amino}methyl)phenyl]-N-methylmethanesulfonamidehydrochloride;N-[2-({[6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-pyrazolo[4,3-c]pyridin-4-yl]amino}methyl)-3-fluorophenyl]-N-methylmethanesulfonamidehydrochloride;N-[2-({[6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-pyrazolo[4,3-c]pyridin-4-yl]amino}methyl)-phenyl]-N-methylethanesuIfonamide hydrochloride;N-ethyl-N-[2-({[6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-pyrazolo[4,3-c]pyridin-4-yl]amino}-methyl)phenyl]ethanesulfonamidehydrochloride;N-[2-({[6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-pyrazolo[4,3-c]pyridin-4-yl]amino}methyl)phenyl]-N-propylmethanesulfonamide;N-ethyl-N-[2-({[6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-pyrazolo[4,3-c]pyridin-4-yl]amino}-methyl)phenyl]methanesulfonamide;N-butyl-N-[2-({[6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-pyrazolo[4,3-c]pyridin-4-yl]amino}-methyl)phenyl]methanesulfonamide;N-[2-({[6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-pyrazolo[4,3-c]pyridin-4-yl][2-(morpholin-4-yl)ethyl]amino}methyl)phenyl]-N-methylmethanesulfonamide;N-[2-({[6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-pyrazolo[4,3-c]pyridin-4-yl][2-(morpholin-4-yl)ethyl]amino}methyl)phenyl]-N-methylmethanesulfonamide;N-ethyl-N-[2-({[6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-pyrazolo[4,3-c]pyridin-4-yl](methyl)-amino}methyl)-4-methylphenyl]methanesulfonamide;N-[2-({ethyl[6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-pyrazolo[4,3-c]pyridin-4-yl]amino}methyl)-4-methylphenyl]-N-methylmethanesulfonamide;N-[2-({[6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-pyrazolo[4,3-c]pyridin-4-yl](propyl)amino}-methyl)-4-methylphenyl]-N-methylmethanesulfonamide;N-ethyl-N-[2-({[6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-pyrazolo[4,3-c]pyridin-4-yl](methyl)amino}methyl)phenyl]methanesulfonamidehydrochloride;N-[2-({[6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-pyrazolo[4,3-c]pyridin-4-yl](methyl)amino}-methyl)phenyl]-N-methylmethanesulfonamidehydrochloride;N-[2-({[6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-pyrazolo[4,3-c]pyridin-4-yl]amino}methyl)phenyl]-N-(2-hydroxyethyl)methanesulfonamide;N-{2-[({6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-1H-pyrazolo[4,3-c]pyridin-4-yl}amino)methyl]phenyl}-N-methylmethanesulfonamide;N-(2-{[{6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-1H-pyrazolo[4,3-c]pyridin-4-yl}(methyl)amino]methyl}phenyl)-N-methylmethanesulfonamide;N-{2-[({6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-1H-pyrazolo[4,3-c]pyridin-4-yl}amino)methyl]-4-methylphenyl}-N-methylmethanesulfonamide;4-{4-[(cyclopropylmethyl)amino]-1H-pyrazolo[3,4-d]pyrimidin-6-yl}-2-fluoro-5-(2,2,2-trifluoroethyl)phenol;4-{4-[(2-cyclopropylethyl)amino]-1H-pyrazolo[3,4-d]pyrimidin-6-yl}-2-fluoro-5-(2,2,2-trifluoroethyl)phenol;2-fluoro-4-{4-[(2-methylpropyl)amino]-1H-pyrazolo[3,4-d]pyrimidin-6-yl}-5-(2,2,2-trifluoro-ethyl)phenol;4-[4-(butylamino)-1H-pyrazolo[3,4-d]pyrimidin-6-yl]-2-fluoro-5-(2,2,2-trifluoroethyl)phenol;N-[2-({[6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]amino}methyl)-phenyl]-N-methylmethanesulfonamidehydrochloride;N-(2-(((6-(2-ethyl-4-hydroxy-6-methylphenyl)-1H-pyrazolo[4,3-c]pyridin-4-yl)amino)methyl)-phenyl)-N-methylmethanesulfonamide;N-[2-({[6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-3-(1H-imidazol-2-yl)-1H-pyrazolo[4,3-c]pyridin-4-yl]amino}methyl)phenyl]-N-methylmethanesulfonamide;N-[2-({[3-(4,5-dimethyl-1H-imidazol-2-yl)-6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-pyrazolo[4,3-c]pyridin-4-yl]amino}methyl)phenyl]-N-methylmethanesulfonamide;N-[2-({[6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-3-(4-methyl-1H-imidazol-2-yl)-1H-pyrazolo[4,3-c]pyridin-4-yl]amino}methyl)phenyl]-N-methylmethanesulfonamide;4-[3-(5-benzyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yl)-4-{[2-(methylsulfanyl)ethyl]-amino}-1H-pyrazolo[4,3-c]pyridin-6-yl]-2-fluoro-5-(2,2,2-trifluoroethyl)phenol;N-[2-({[6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-3-(1H-pyrazol-1-yl)-1H-pyrazolo[4,3-c]pyridin-4-yl]amino}methyl)phenyl]-N-methylmethanesulfonamide;N-(2-[({6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-3-(1H-pyrazol-1-yl)-1H-pyrazolo[4,3-c]pyridin-4-yl}amino)methyl]phenyl}-N-methylmethanesulfonamide;N-{2-[({6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-3-(5-methyl-4H-1,2,4-triazol-3-yl)-1H-pyrazolo[4,3-c]pyridin-4-yl}amino)methyl]phenyl}-N-methylmethanesulfonamide;N-[2-({[6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-3-(5-methyl-4H-1,2,4-triazol-3-yl)-1H-pyrazolo[4,3-c]pyridin-4-yl]amino}methyl)phenyl]-N-methylmethanesulfonamide;N-{2-[({6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-3-[5-(6-methylpyridin-3-yl)-4H-1,2,4-triazol-3-yl]-1H-pyrazolo[4,3-c]pyridin-4-yl}amino)methyl]phenyl}-N-methylmethanesulfonamide;4-(5-{6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-4-({5-hydroxy-2-[methyl(methyl-sulfonyl)amino]benzyl}amino)-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-4H-1,2,4-triazol-3-yl)piperidine-1-carboxamide;N-(2-{[(6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-3-{5-[1-(pyrrolidin-1-ylacetyl)pipendin-4-yl]-4H-1,2,4-triazol-3-yl}-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino]methyl}phenyl)-N-methyl-methanesulfonamide;N-{2-[({6-[5-fluoro-4-hydroxy-2-(2, 2, 2-trifluoroethyl)phenyl]-3-(4, 5,6, 7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl}amino)methyl]-4-hydroxyphenyl}-N-methylmethanesulfonamide;N-{2-[({3-(5-acetyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yl)-6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-4-yl}amino)methyl]-4-hydroxyphenyl}-N-methylmethanesulfonamide;N-[2-(dimethylamino)ethyl]-2-{6-[5-fluoro-4-hydroxy-2-(2,2,2-trifluoroethyl)phenyl]-4-({5-hydroxy-2-[methyl(methylsulfonyl)amino]benzyl}amino)-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxamide; and,4-(3-(5-benzyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yl)-4-((3-hydroxy-2-methylpropyl)-amino)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-2-fluoro-5-(2,2,2-trifluoroethyl)phenol.